Small Cell Lung Cancer Patient-derived Xenograft Models Research Articles

Abstract 606: The PLK1 inhibitor, onvansertib, synergizes with paclitaxel in small cell lung cancer

Abstract Background: Small cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with rapid disease progression and poor patient survival. Therapeutic options for SCLC remain a challenge due to limited understanding of both the biology of the disease and the major determinants of treatment response. Key transcription factors associated with unique biological phenotypes of SCLC include ASCL1, NEUROD1, YAP1, and POU2F3. Previously, we demonstrated that onvansertib, a highly specific inhibitor of the PLK1 Ser/Thr kinase, was effective in SCLC preclinical models, leading to its ongoing clinical development for relapsed/refractory SCLC patients (NCT05450965). Here we further explored potential strategies to enhance onvansertib activity by assessing its in vitro and in vivo activity in combination treatments. Methods: Human SCLC cell lines were treated for 72 hr with onvansertib in combination with paclitaxel, lurbinectedin or the ATR inhibitors BAY1895344 and AZD6738. Effect on cell proliferation was analyzed by WST1 and CellTiterGlo assays. In vivo activity of onvansertib in combination with paclitaxel was tested in 3 SCLC patient-derived xenograft (PDX) models either cisplatin-sensitive (TKO5- ASCL1 subtype) or cisplatin-resistant (TKO2-ASCL1 subtype, TKO8-NEUROD1 subtype). Tumor-bearing nude mice were treated with vehicle, onvansertib (50 mg/kg, oral, 4 times/week), paclitaxel (15 mg/kg, IP, once a week) or the combination for 5 weeks. Mice were followed for tumor growth and survival (defined as time to reach tumor volume greater than 2000 mm3). Results: The combination of onvansertib and paclitaxel inhibited cell proliferation synergistically in cell lines from 3 SCLC subtypes (ASCL1, NEUROD1, and YAP1), while the combinations with lurbinectedin or ATR inhibitors were not synergistic. We further examined the combination of onvansertib and paclitaxel in SCLC PDXs. The combination exhibited potent anti-tumor activity, resulting in significantly greater tumor growth inhibition and increase in survival compared to the monotherapies in all 3 PDXs. The combination was well tolerated with no observed body weight loss. While onvansertib and paclitaxel had negligible single agent activity in cisplatin-resistant TK02 PDX and TKO8 PDX models, the combination induced durable complete responses in 25% and 100% of treated mice respectively. Conclusion: The PLK1 inhibitor onvansertib in combination with paclitaxel showed synergy in multiple SCLC cell lines in vitro and potent anti-tumor activity in cisplatin-sensitive and -resistant SCLC PDX models in vivo. Tumor tissue analysis is underway to detail the mechanisms of this interaction. Citation Format: John C. Schmitz, Guojing Zhang, Abbe Pannucci, Tod Smeal, Chu-Chiao Wu, Maya Ridinger, Taofeek K. Owonikoko. The PLK1 inhibitor, onvansertib, synergizes with paclitaxel in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 606.

Abstract LB_A22: Advancing personalized therapies for small cell lung cancer: Exploring HER2-targeting antibody-drug conjugates (ADCs) and SLFN11 biomarker insights

Abstract Background: Small-cell lung cancer (SCLC) is a highly aggressive malignancy constituting 15% of all lung cancers, with a 5-year survival rate of less than 7%. Our group has established four transcriptionally defined subtypes of SCLC, each with distinct cell surface targets (Gay et al, Cancer Cell 2021). Further, we identified SLFN11 (a putative DNA/RNA helicase) as a candidate biomarker of sensitivity to DNA-damaging agents, including topoisomerase I inhibitors. Despite these advances, SCLC is still treated clinically with a “one-size-fits-all” approach. Human epidermal growth factor receptor 2 (HER2/ERBB2) has been previously described in a subset of SCLCs and has been linked to poor prognosis. Notably, HER2-targeting antibody-drug conjugates (ADCs) like Trastuzumab Deruxtecan (T-DXd) (where the payload is a topoisomerase I inhibitor) have received FDA approval for various solid tumors, highlighting their therapeutic potential. Methods: We analyzed ERBB2 mRNA expression in publicly available patient datasets and profiled HER2 protein expression in cell lines and patient-derived xenograft models by flow cytometry and IHC. We then assessed the cytotoxicity of Trastuzumab Deruxtecan in a panel of cell lines representative of the heterogeneity of SCLC to test whether levels of HER2 and/or SLFN11 predicted response. Results: Analyses of HER2/ERBB2 in SCLC cell lines and patient-derived xenograft (PDX) models revealed an enrichment in the SCLC-POU2F3 (SCLC-P) subtype. HER2 expression was validated by IHC and flow cytometry in a subset of SCLC cell lines and PDX models. ERBB2 mRNA expression data was analyzed using publicly available SCLC patient datasets, where we uncovered high expression of ERBB2 in a subset of patient tumors. Consistent with this, single-cell RNA-Seq data revealed ERBB2 expression in POU2F3+ cells in tumors from patients with relapsed SCLC. As predicted, we found a strong correlation between the in vitro cytotoxicity of Trastuzumab Deruxtecan and both the level of surface HER2 expression and SLFN11 level. Importantly, the SCLC cell lines with the highest HER2 surface expression exhibited the lowest IC50 of Trastuzumab Deruxtecan, and the response was predicted by the presence of SLFN11. Conclusion: We demonstrate HER2/ERBB2 mRNA and protein expression in a subset of SCLC, with enrichment in the SCLC-P subtype. Further, the FDA-approved HER2-targeting ADC Trastuzumab Deruxtecan had significant cytotoxicity, correlating with expression of the surface target (HER2) as well as with SLFN11 (a candidate predictive biomarker for the topoisomerase inhibitor payload). These findings suggest the potential of tailoring HER2-targeting strategies based on HER2 and SLFN11 expression in SCLC as an effective and personalized approach for tackling SCLC. Citation Format: Ali H. Ibrahim, Bingnan Zhang, C. Allison Stewart, Alejandra Serrano, Luisa M. Solis, Wei-Lien Wang, Kavya Ramkumar, Robert J. Cardnell, Runsheng Wang, Alberto Duarte Jr, Lixia Diao, Yuanxin Xi, Jing Wang, Lauren A. Byers, Carl M. Gay. Advancing personalized therapies for small cell lung cancer: Exploring HER2-targeting antibody-drug conjugates (ADCs) and SLFN11 biomarker insights [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_A22.

De Novo and Histologically Transformed Small-Cell Lung Cancer Is Sensitive to Lurbinectedin Treatment Through the Modulation of EMT and NOTCH Signaling Pathways.

Small-cell lung cancer (SCLC) is a high-grade neuroendocrine tumor with dismal prognosis and limited treatment options. Lurbinectedin, conditionally approved as a second-line treatment for metastatic SCLC, drives clinical responses in about 35% of patients, and the overall survival (OS) of those who benefit from it remains very low (∼9.3 months). This finding highlights the need to develop improved mechanistic insight and predictive biomarkers of response. We used human and patient-derived xenograft (PDX)-derived SCLC cell lines to evaluate the effect of lurbinectedin in vitro. We also demonstrate the antitumor effect of lurbinectedin in multiple de novo and transformed SCLC PDX models. Changes in gene and protein expression pre- and post-lurbinectedin treatment was assessed by RNA sequencing and Western blot analysis. Lurbinectedin markedly reduced cell viability in the majority of SCLC models with the best response on POU2F3-driven SCLC cells. We further demonstrate that lurbinectedin, either as a single agent or in combination with osimertinib, causes an appreciable antitumor response in multiple models of EGFR-mutant lung adenocarcinoma with histologic transformation to SCLC. Transcriptomic analysis identified induction of apoptosis, repression of epithelial-mesenchymal transition, modulation of PI3K/AKT, NOTCH signaling associated with lurbinectedin response in de novo, and transformed SCLC models. Our study provides a mechanistic insight into lurbinectedin response in SCLC and the first demonstration that lurbinectedin is a potential therapeutic target after SCLC transformation.

Targeting BCL2 Overcomes Resistance and Augments Response to Aurora Kinase B Inhibition by AZD2811 in Small Cell Lung Cancer.

Therapeutic resistance to frontline therapy develops rapidly in small cell lung cancer (SCLC). Treatment options are also limited by the lack of targetable driver mutations. Therefore, there is an unmet need for developing better therapeutic strategies and biomarkers of response. Aurora kinase B (AURKB) inhibition exploits an inherent genomic vulnerability in SCLC and is a promising therapeutic approach. Here, we identify biomarkers of response and develop rational combinations with AURKB inhibition to improve treatment efficacy. Selective AURKB inhibitor AZD2811 was profiled in a large panel of SCLC cell lines (n = 57) and patient-derived xenograft (PDX) models. Proteomic and transcriptomic profiles were analyzed to identify candidate biomarkers of response and resistance. Effects on polyploidy, DNA damage, and apoptosis were measured by flow cytometry and Western blotting. Rational drug combinations were validated in SCLC cell lines and PDX models. AZD2811 showed potent growth inhibitory activity in a subset of SCLC, often characterized by, but not limited to, high cMYC expression. Importantly, high BCL2 expression predicted resistance to AURKB inhibitor response in SCLC, independent of cMYC status. AZD2811-induced DNA damage and apoptosis were suppressed by high BCL2 levels, while combining AZD2811 with a BCL2 inhibitor significantly sensitized resistant models. In vivo, sustained tumor growth reduction and regression was achieved even with intermittent dosing of AZD2811 and venetoclax, an FDA-approved BCL2 inhibitor. BCL2 inhibition overcomes intrinsic resistance and enhances sensitivity to AURKB inhibition in SCLC preclinical models.

Abstract LB233: Preclinical analysis identifies predictive biomarker and potential pathways of resistance to lurbinectedin treatment in small cell lung cancer

Abstract Background: Small cell lung cancer (SCLC) is an exceptionally aggressive disease with limited treatment options that typically result in transient responses. SCLC is responsible for approximately 250,000 deaths globally per year. Major hurdles to improving SCLC treatment include the development of rapid chemo-resistance and limited second-line therapies. Lurbinectedin is FDA approved as a second-line treatment for SCLC but shows a response in a subset of patients. Therefore, improved mechanistic understanding and identifying predictive biomarkers of lurbinectedin treatment is a major unmet clinical need. Methods: We treated SCLC cell lines and patient-derived xenograft (PDX) models from all major SCLC subtypes with lurbinectedin. Lurbinectedin-mediated changes in signaling pathways were studied by bulk RNA sequencing, western blot, and flow cytometry. Anti-tumor efficacy and toxicity studies were performed in vivo. Result: All human and PDX-derived SCLC cell lines showed sensitivity to lurbinectedin at a nano-molar concentration ranging from 1.905 to 30 nM. Bulk RNA-seq analysis showed lurbinectedin induced changes in neuroendocrine phenotype, DNA damage response and tumor progression markers in vitro. Single agent treatment of lurbinectedin showed remarkable anti-tumor efficacy in an ASCL1-driven PDX model. RNA sequencing analysis identified modulation of genes in multiple signaling pathways including PI3K-AKT, apoptosis and EMT to be significantly associated with the lurbinectedin response in PDX models. Conclusion: There is an immediate need to understand the subsets of SCLC that would be most sensitive to lurbinectedin and identify predictive biomarkers. We demonstrate MYC as a predictive biomarker for lurbinectedin response. We are the first to show that single agent lurbinectedin shows remarkable anti-tumor efficacy in a ASCL1-driven PDX models of SCLC. Furthermore, our pre and post-lurbinectedin treatment transcriptomic analysis identify the pathways that may contribute to primary or acquired resistance to lurbinectedin in SCLC. Finally, we identity candidate targets that would guide the design of future combination clinical trials with lurbinectedin in SCLC. Citation Format: Subhamoy Chakraborty, Charles Coleman, Deniz Demircioglu, Dan Hasson, Triparna Sen. Preclinical analysis identifies predictive biomarker and potential pathways of resistance to lurbinectedin treatment in small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr LB233.

The First-in-Class UBA1 Inhibitor, TAK-243, in Combination With Radiotherapy for YAP1 and BEND3 Biomarker-Defined Small Cell Lung Cancer

The First-in-Class UBA1 Inhibitor, TAK-243, in Combination With Radiotherapy for YAP1 and BEND3 Biomarker-Defined Small Cell Lung Cancer

AMG 757, a Half-Life Extended, DLL3-Targeted Bispecific T-Cell Engager, Shows High Potency and Sensitivity in Preclinical Models of Small-Cell Lung Cancer.

Small-cell lung cancer (SCLC) is an aggressive neuroendocrine tumor with a high relapse rate, limited therapeutic options, and poor prognosis. We investigated the antitumor activity of AMG 757, a half-life extended bispecific T-cell engager molecule targeting delta-like ligand 3 (DLL3)-a target that is selectively expressed in SCLC tumors, but with minimal normal tissue expression. AMG 757 efficacy was evaluated in SCLC cell lines and in orthotopic and patient-derived xenograft (PDX) mouse SCLC models. Following AMG 757 administration, changes in tumor volume, pharmacodynamic changes in tumor-infiltrating T cells (TILs), and the spatial relationship between the appearance of TILs and tumor histology were examined. Tolerability was assessed in nonhuman primates (NHPs). AMG 757 showed potent and specific killing of even those SCLC cell lines with very low DLL3 expression (<1,000 molecules per cell). AMG 757 effectively engaged systemically administered human T cells, induced T-cell activation, and redirected T cells to lyse tumor cells to promote significant tumor regression and complete responses in PDX models of SCLC and in orthotopic models of established primary lung SCLC and metastatic liver lesions. AMG 757 was well tolerated with no AMG 757-related adverse findings up to the highest tested dose (4.5 mg/kg weekly) in NHP. AMG 757 exhibits an extended half-life in NHP, which is projected to enable intermittent administration in patients. AMG 757 has a compelling safety and efficacy profile in preclinical studies making it a viable option for targeting DLL3-expressing SCLC tumors in the clinical setting.

TAK-243 Combined With Radiation And Other DNA Damaging Agents As A Novel Therapeutic Strategy For Small Cell Lung Cancer

Small cell lung cancer (SCLC) (∼15-17% of lung cancer) is an aggressive disease, with a dismal overall five-year survival of 7%. The current first-line therapy consisting of cisplatin and etoposide chemotherapy (C/E) +/- radiation (RT), has changed minimally in >30 years. TAK-243, an E1 ubiquitin activating enzyme (UAE) inhibitor, is a promising novel SCLC therapy. TAK-243 limits the formation of ubiquitin conjugates that mediate many cellular processes including DNA repair signaling. By dysregulating cancer-specific dependencies of UAE, TAK-243 may induce malignant cell death and potentiate DNA damage induced by RT and chemotherapeutic agents. Initial findings show TAK-243 is particularly effective for 2 SCLC cell-lines (EC50 of 0.006 - 0.011mM), compared to other cancers and normal tissues (n = 29, EC50 ranging from 0.012 to 1.31mM; Hyer et al., 2018). However, TAK-243 has not been comprehensively evaluated as a single agent or in combination with C/E and RT for SCLC. SCLC cell-lines were treated with incremental doses of TAK-243 (0-1mM) and viability was determined by a resazurin conversion assay after 6 days. EC50 values were compared. To evaluate combination effects, C/E were administered (1:1 ratio, 0-1mM) to cell-lines together with a fixed cell-line specific TAK-243 dose (EC30). Area under the curve (AUC) was compared between TAK-243+C/E and C/E-alone groups. TAK-243 (0-1mM) was administered with RT (2-8 Gy) in a similar manner and cell viability was measured after 9 days. Dose modification factor (DMF), the ratio of RT dose required between control and drug-treated groups, was calculated at survival fraction 37. TAK-243 single agent therapy (20mg/kg, BIW) was evaluated in a patient-derived xenograft (PDX) SCLC model (SCRX-Lu149). Subcutaneous tumors were established, and tumor volumes were compared between experimental and control conditions. Kaplan-Meier survival analysis and significance testing using the Log-Rank Test were completed. Single-agent therapy. EC50 values of SCLC cell-lines (n = 11) ranged from 0.003-0.12mM in vitro. TAK-243-treated animals experienced significantly increased freedom from volumetric endpoint (p-value = 0.028) when evaluated in vivo. TAK-243+Chemotherapy. Treatment revealed a positive combination effect for the majority of SCLC cell-lines (n = 5, ΔAUC from -13-47 units), suggesting potential chemosensitivity. TAK-243+Radiotherapy. Potential radiosensitization was observed in all SCLC cell-lines (n = 5) as tested by the resazurin assay (DMF from 1.25-1.35). Cell-line and PDX models of SCLC are sensitive to TAK-243. With TAK-243, lower doses of C/E and RT are required for most cell-lines. Use of TAK-243 may be a novel strategy to improve SCLC therapies. These findings will be validated using clonogenic survival assays and interrogated in vivo, which may provide a basis to move TAK-243 to the clinic.

Abstract 1060: Genetic and pharmacologic inhibition of Skp2, an E3 ubiquitin ligase and RB1-target, has antitumor activity in RB1-deficient human and mouse small cell lung cancer (SCLC)

Abstract The identification of driver mutations and their corresponding targeted drugs has led to significant improvements in the treatment of non-small cell lung cancer (NSCLC) and other solid tumors; however, similar advances have not been made in the treatment of small cell lung cancer (SCLC). Due to their aggressive growth, frequent metastases, and resistance to chemotherapy, the five-year overall survival of SCLC is less than 5%. While SCLC tumors can be sensitive to first-line therapy of cisplatin and etoposide, most patients relapse, often in less than 3 months after initial therapy. Dozens of drugs have been tested clinically in SCLC, including more than 40 agents that have failed in phase III trials. The near uniform bi-allelic inactivation of the tumor suppressor gene RB1 is a defining feature of SCLC. RB1 is mutated in highly aggressive tumors, including SCLC, where its functional loss, along with that of TP53, is both required and sufficient for tumorigenesis. While it is known that RB1 mutant cells fail to arrest at G1/S in response to checkpoint signals, this information has not led to effective strategies to treat RB1-deficient tumors, and it has been challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/p53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, and we confirmed this was the mechanism of protection in the RP-Skp2 KO mice by using the knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind to and/or inhibit Skp2 induced apoptosis and inhibited SCLC cell growth. In a panel of SCLC cell lines, growth inhibition by a Skp2 inhibitor was not correlated with sensitivity/resistance to etoposide. Targeting Skp2 also had in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using the genetic and pharmacologic approaches, antitumor activity was seen in vivo in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. The identification and validation of an actionable target downstream of RB1 could have a broad impact on treatment of SCLC and other advanced tumors with mutant RB1, for which there are currently no targeted therapies available. Citation Format: Hongling Zhao, Vineeth Sukrithan, Niloy Iqbal, Cari Nicholas, Yingjiao Xue, Joseph Locker, Juntao Zou, Liang Zhu, Edward L. Schwartz. Genetic and pharmacologic inhibition of Skp2, an E3 ubiquitin ligase and RB1-target, has antitumor activity in RB1-deficient human and mouse small cell lung cancer (SCLC) [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1060.

Targeted Inhibition of the E3 Ligase SCFSkp2/Cks1 Has Antitumor Activity in RB1-Deficient Human and Mouse Small-Cell Lung Cancer.

The RB1 tumor suppressor gene is mutated in highly aggressive tumors including small-cell lung cancer (SCLC), where its loss, along with TP53, is required and sufficient for tumorigenesis. While RB1-mutant cells fail to arrest at G1-S in response to cell-cycle restriction point signals, this information has not led to effective strategies to treat RB1-deficient tumors, as it is challenging to develop targeted drugs for tumors that are driven by the loss of gene function. Our group previously identified Skp2, a substrate recruiting subunit of the SCF-Skp2 E3 ubiquitin ligase, as an early repression target of pRb whose knockout blocked tumorigenesis in Rb1-deficient prostate and pituitary tumors. Here we used genetic mouse models to demonstrate that deletion of Skp2 completely blocked the formation of SCLC in Rb1/Trp53-knockout mice (RP mice). Skp2 KO caused an increased accumulation of the Skp2-degradation target p27, a cyclin-dependent kinase inhibitor, which was confirmed as the mechanism of protection by using knock-in of a mutant p27 that was unable to bind to Skp2. Building on the observed synthetic lethality between Rb1 and Skp2, we found that small molecules that bind/inhibit Skp2 have in vivo antitumor activity in mouse tumors and human patient-derived xenograft models of SCLC. Using genetic and pharmacologic approaches, antitumor activity was seen with Skp2 loss or inhibition in established SCLC primary lung tumors, in liver metastases, and in chemotherapy-resistant tumors. Our data highlight a downstream actionable target in RB1-deficient cancers, for which there are currently no targeted therapies available. SIGNIFICANCE: There are no effective therapies for SCLC. The identification of an actionable target downstream of RB1, inactivated in SCLC and other advanced tumors, could have a broad impact on its treatment.

Abstract C091: Preclinical evaluation of PK, PD, and antitumor activity of the oral, non-covalent, potent and highly selective CDK7 inhibitor, SY-5609, provides rationale for clinical development in multiple solid tumor indications

Abstract Introduction: CDK7 is a key regulator of transcription and cell cycle progression and has been implicated in multiple tumor types driven by aberrant transcriptional control (e.g. MYC-, ESR1-activation) and/or aberrant cell cycle control (e.g. RB1, CCNE1, CDKN2A alterations). SY-5609 is an oral, potent, and highly selective CDK7 inhibitor that is advancing through IND-enabling studies to support initiation of a planned Phase 1 oncology trial in early 2020. Here we report on the relationship between pharmacokinetics (PK), pharmacodynamics (PD), and tumor growth inhibition (TGI) in xenograft models of tumor types with transcriptional and/or cell cycle aberrations including high grade serous ovarian cancer (HGSOC), small cell lung cancer (SCLC), triple negative breast cancer (TNBC), and estrogen receptor positive breast cancer (ER+BC). Methods: The relationship between SY-5609 PK, PD, and TGI was evaluated in xenograft models of HGSOC (OVCAR3) and TNBC (HCC70) using once daily (QD) or twice daily (BID) dosing via oral gavage. SY-5609 TGI was evaluated as a single agent (SA) QD in patient-derived xenograft (PDX) models of HGSOC (n=3), SCLC (n=4), TNBC (n=4), and in combination with once weekly fulvestrant in ER+BC PDX models selected in vivo for resistance to the CDK4/6 inhibitor palbociclib (n=1) or resistance to both palbociclib and fulvestrant (n=1). Results: SY-5609 plasma exposure was dose proportional and did not accumulate after repeated therapeutic doses. Dose-dependent transcriptional responses in xenograft tissue were observed within 4 hours of SY-5609 dosing and were sustained for 24 hours. TGI was dose-dependent, with tumor regressions observed at doses significantly below the maximum tolerated dose (MTD). Similar TGI was seen when the same daily dose was administered either QD or BID suggesting that the effect was driven by overall exposure or minimum concentration. In HGSOC, SCLC, and TNBC PDX models, SA SY-5609 induced &amp;gt;50% TGI in all models tested (11/11), with 7/11 (64%) demonstrating robust anti-tumor activity (≥90% TGI or regression): 3/3 HGSOC, 2/4 SCLC, and 2/4 TNBC. In a palbociclib-resistant ER+BC PDX model, the combination of SY-5609 and fulvestrant induced significant TGI (89%), with no evident tumor regrowth up to 21 days after dosing cessation, distinguishing the observed effects from SY-5609 SA or fulvestrant SA. In a palbociclib and fulvestrant double-resistant ER+ BC PDX model, SY-5609 SA resulted in 33% TGI and fulvestrant SA had no activity. In contrast, the combination of SY-5609 and fulvestrant demonstrated significant TGI (68%; p&amp;lt;0.0001 vs fulvestrant SA), suggesting re-sensitization to fulvestrant. Conclusions: We have characterized PK, PD, and anti-tumor activity of the CDK7 inhibitor SY-5609 in a series of xenograft models. Exposure in plasma is dose-proportional and does not accumulate at therapeutic dose levels. SY-5609 induces dose-dependent transcriptional responses in tumor xenograft tissue and shows robust TGI, including regressions, in PDX models derived from multiple solid tumor indications. These results highlight the broad potential for SY-5609 across a variety of solid tumor types, including treatment resistant ER+BC, and support the development of SY-5609 in early phase clinical trials. Citation Format: Liv H Johannessen, Shanhu Hu, Nan Ke, Anthony D'Ippolito, Nisha Rajagopal, Jason Marineau, Anneli Savinainen, William Zamboni, Graeme Hodgson. Preclinical evaluation of PK, PD, and antitumor activity of the oral, non-covalent, potent and highly selective CDK7 inhibitor, SY-5609, provides rationale for clinical development in multiple solid tumor indications [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C091. doi:10.1158/1535-7163.TARG-19-C091

Abstract 381: Combined inhibition of Bcl-2 and MCL-1 in small cell lung cancer (SCLC) is most effective in tumors with low Bcl-xL expression

Abstract Introduction: SCLC is an aggressive high-grade neuroendocrine malignancy in which targeting anti-apoptotic regulators such as Bcl-2 and Bcl-xL has shown efficacy in pre-clinical models but has not resulted in successful clinical trials (Rudin et al., Clin Cancer Res. 2012). Although SCLC cell-lines do not reflect the clinical impact of these inhibitors, patient-derived xenograft (PDX) models may more accurately recapitulate Bcl-2 family expression profiles and BH3 mimetic efficacy. One promising hypothesis is that the fellow anti-apoptotic protein MCL-1 rescues viability in the presence of Bcl-2/Bcl-xL antagonists. Here we evaluate the efficacy of the MCL-1 inhibitor S63845 in combination with a novel specific inhibitor of Bcl-2, BCL201/S55746, in SCLC patient-derived xenografts. Methods: BH3 mimetic compounds were tested for synergy in vitro in SCLC cell lines. A set of ten cell lines was chosen based on relative expression of BCL2, MCL1, and BCL2L1 (Bcl-xL) mRNA. Single agent and and pair-wise combinations of Bcl2 family inhibitors were compared in three-day growth inhibition assays. Loewe synergy scores were plotted versus Bcl2 family mRNA expression to identify the determinants of drug sensitivity. Based on the cell line synergy assays, a combination of BCL201/S55746 and S63845 was selected to test in PDX models of SCLC. Bcl-2 family expression was profiled across a panel of 37 SCLC PDX models generated at MGH by quantitative western blot, and standardized to the most sensitive SCLC cell line, NCI-H211. Ten models were selected based on absolute expression of Bcl-2, Bcl-xL and MCL-1. Mice were treated when subcutaneous tumors reached a volume of 400-800 cc, enabling precise measurement of tumor regression and time to tumor regrowth. Findings: Bcl-2 family dependency in SCLC cell lines was profiled with selective inhibitors as single agents or combinations. Maximum synergy was found between BCL201/S55746 and S63845 in cell lines with the highest Bcl-2:Bcl-xL expression ratio. Bcl-2 family expression was profiled across a panel of 37 PDX models of SCLC, and a representative set of 10 models was selected for in vivo testing. Consistent with cell line results, the two most sensitive models to BCL201/S55746+S63845 demonstrated the highest Bcl-2:Bcl-xL ratios, with moderate to high expression of MCL-1. In these models BCL201/S55746+S63845 resulted in a 44-70% tumor regression that was stable throughout 4 weeks of treatment. Efficacy was not dependent on MCL-1 expression, and was not strongly correlated with PDX sensitivity to platinum-etoposide. Conclusions: Combined inhibition of Bcl-2 with BCL201 and MCL-1 with S63845 is effective in SCLC tumors with relatively low Bcl-xL expression. This combination overcomes MCL-1 mediated resistance to Bcl-2 inhibitors, and represents a promising strategy to target anti-apoptotic dependency in SCLC. Citation Format: Benjamin J. Drapkin, Sneha Sanghavi, David T. Myers, Jun Zhong, Sarah Phat, Youzhen Wang, Ensar Halilovic, Javad Golji, Anna Farago, Erick Morris, Nicholas J. Dyson. Combined inhibition of Bcl-2 and MCL-1 in small cell lung cancer (SCLC) is most effective in tumors with low Bcl-xL expression [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 381.

Abstract 2699: Targeting an ubiquitin-activating enzyme in small-cell lung cancer (SCLC)

Abstract Background: Despite valiant efforts to improve patient outcomes, small cell lung cancer (SCLC) (~15-17% of lung cancer) remains an aggressive lung cancer, with an overall five-year survival of 7%. Current first-line therapy (chemotherapy+/-radiation) has not changed in 30+ years. TAK-243, an inhibitor of the ubiquitin activating enzyme (UAE), E1 (encoded by UBA1), poses a novel approach for cancer therapy. TAK-243 limits the formation of ubiquitin conjugates that ultimately mediate many cellular processes, including DNA repair signalling and protein degradation. Consequently, TAK-243 may disrupt cancer-specific dependencies of UAE to induce malignant cell death, and potentiate radiation-induced DNA damage. The discovery publication revealed that TAK-243 is especially potent in 2 SCLC cell-lines compared to healthy breast and fibroblastic tissues. With these limited data, the potential benefit of this novel agent as monotherapy and in combination with chemotherapy for SCLC has yet to be elucidated. Methods: We assessed the anti-proliferative effect of TAK-243 monotherapy in a large panel (n = 10) of variant and classical SCLC cell-lines, including assorted MYC family member amplifications and different UBA1 mRNA expression levels. TAK-243 EC50 single agent doses were determined by treating cell-lines with incremental concentrations of TAK-243 (0-1μM). For combinatorial analysis, TAK-243 (0-1μM) was administered to cell-lines alongside cisplatin/etoposide (CE) at cell-line specific optimized doses yielding 30-35% kill by CE. Short-term efficacy was determined by a cell viability resazurin assay, 48 hours after treatment initiation. ΔEC50 was measured as the single agent EC50 subtracted by the EC50 of TAK-243+CE. Positive ΔEC50 values show potential synergy between TAK-243 and CE. Results: Single-agent therapy. SCLC cell-lines demonstrated a range of sensitives to TAK-243 monotherapy after 48 hours. The cell-lines tested are ranked from highest to lowest sensitivity: NCI-H82, NCI-H69, NCI-H1618, LX22 (ex-vivo cultured PDX), NCI-H1092, NCI-H446, SHP77 and NCI-H196; with EC50 values ranging from 18nM to 80nM. However, NCI-H526, NCI-H889, and SBC-5 were non-responsive to therapy at 1μM. Combination therapy. TAK-243 upon combination treatment with CE revealed ΔEC50 values ranging from 5.23-14.54nM. NCI-H82, NCI-H69, SHP77 and NCI-H1092 demonstrated potential chemosensitivity to combination treatment. Conclusions: These data begin to hint at synergy between TAK-243 and CE, where lower doses of TAK-243 may be required for certain SCLC cell-lines when used in combination. These preliminary results suggest that TAK-243 may have the potential to improve the current SCLC standard therapies in molecular defined subgroups. These results are being confirmed in additional cell-lines and through in vivo experiments using patient-derived xenograft models of SCLC. *S.M and M.K.A contributed equally to this work Citation Format: Safa Majeed, Mansi K. Aparnathi, Lifang Song, Aaron D. Schimmer, Ming S. Tsao, Geoffrey Liu, Benjamin H. Lok. Targeting an ubiquitin-activating enzyme in small-cell lung cancer (SCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2699.

Abstract 4736: Dose optimization of olaparib plus temozolomide in small cell lung cancer (SCLC) patient-derived xenograft (PDX) models for clinical translation

Abstract Introduction: SCLC is an aggressive high-grade neuroendocrine malignancy in which targeting DNA-damage repair pathways has shown efficacy in pre-clinical and clinical contexts. We previously conducted a phase I/II trial combining the PARP inhibitor olaparib (O) tablets with the alkylating agent temozolomide (T) in patients with relapsed SCLC, in which O and T were both given days (d) 1-7 of each 21 d cycle. The recommended phase 2 dose (RP2D) was O 200 mg PO BID and T 75 mg/m2 PO daily, and the response rate among the first 29 evaluable patients was 41.4%, with the primary toxicities being hematologic (Farago et al., ASCO 2018). Continuous PARP inhibition with O may improve efficacy, though it is unknown how best to incorporate T onto this backbone. Simultaneous clinical testing of multiple dosing schedules for concurrent OT would be impractical. Here we present an optimization of the OT regimen using PDX models generated from patients treated with OT. Methods: SCLC PDX models derived from two patients prior to their durable responses to OT, MGH1518-1B and MGH1528-1, were used for dose optimization. Based on a human-murine comparison of serum Cmax for OT, the estimated murine-equivalents for the RP2D doses were O 25 mg/kg BID and T 6.25 mg/kg/d. The RP2D regimen was then modulated in both dose intensity and duration in a 9-arm PDX trial. The arms included 3 schedule categories, with doses varied within each category: discontinuous regimens (OT d 1-7); continuous O regimens (O d1-21 + T d 1-7); and rapid- or slow-alternating regimens administering O and T on non-overlapping days. Tumor bearing mice were treated when subcutaneous tumors reached a volume of 400-800 cc, enabling measurement of tumor regression (PDX response) and time to volume doubling (PDX TTP). Findings: The RP2D regimen resulted in near-complete response in both models. This degree of regression was recapitulated with nearly all dosing schedules, and was not improved by increasing T to 2x-RP2D. However, the PDX TTP varied. In both models, the longest TTP was seen with continuous O at full- or half-RP2D and d 1-7 T at half-RP2D. This regimen prolonged TTP by 12% in MGH1518-1B and 20% in MGH1528-1, versus discontinuous OT at RP2D. Based on these results, we initiated clinical treatment in a new cohort of patients on OT, with a phase 1 dose escalation starting with O 50 mg BID d 1-21 and T 50 mg/m2 d 1-7 of each 21 d cycle (NCT02446704). At this first dose level, a partial response by RECIST 1.1 criteria was observed in a heavily pre-treated patient, indicating clinical activity of this combination with this new dosing strategy. Conclusions: In PDX models sensitive to OT at our previously determined RP2D, we find that continuous O with intermittent T permits dose reduction of both O and T without loss of efficacy. A clinical trial is ongoing to determine whether this strategy may enable longer-term dosing and improve efficacy in patients. Citation Format: Benjamin J. Drapkin, Sarah Phat, David T. Myers, Jun Zhong, Beow Y. Yeap, Elisabetta Leo, Anna Stansiszewska, Aaron Smith, Elaine Cadogan, Maria C. Pietanza, Nicholas J. Dyson, Anna Farago. Dose optimization of olaparib plus temozolomide in small cell lung cancer (SCLC) patient-derived xenograft (PDX) models for clinical translation [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4736.

PARP trapping by Talazoparib is a Potent Mechanism of Radiosensitization in Small Cell Lung Cancer Cell Lines and Patient-Derived Xenografts

Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel molecular therapies. We hypothesized that poly(ADP)-ribose polymerase (PARP) inhibitors could effectively sensitize SCLC cells to ionizing radiation (IR). We further hypothesized that PARP trapping, a cytotoxic mechanism of action distinct from inhibition of the PARP enzyme and the DNA damage response, contributes to radiosensitization by PARP inhibitors. Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in six SCLC cell lines. PARP trapping and PARP enzymatic inhibition were analyzed by quantifying the chromatin-bound fraction of PARP1 and the total cell PAR polymer, respectively, using western blot. Doses of veliparib, a weak PARP trapper, and talazoparib, a potent PARP trapper, that had equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. The number of g-H2AX foci induced by veliparib and talazoparib were compared with and without IR using immunofluorescence assays. Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models, and time for the tumors to grow to 1000 mm3 was compared using the log-rank test. Radiosensitization by talazoparib was seen in 5 of 6 cell lines in short term viability assays: one cell line at 0.2 nM (Dose Modification Factor [DMF] 1.56), two cell lines at 2 nM (DMF 1.34 – 1.86), and four cell lines at 20 nM (DMF 1.61 – 2.88). Using CSAs, sensitization to IR was seen in 3 of 3 cell lines, with two cell lines sensitized at 20 nM (DMF 1.40-2.13) and one at 200 nM (DMF 2.20). Doses of 200 nM talazoparib and 1600 nM veliparib similarly inhibited PAR polymerization; however, as expected, talazoparib exhibited greater PARP trapping activity. This dose of veliparib was insufficient for radiosensitization, while the greater PARP trapping observed with 200 nM talazoparib was associated with significant radiosensitization (DMF 3.3). This further correlated with more double-stranded DNA breaks (g-H2AX foci) seen with talazoparib compared to veliparib both in the absence of IR (mean foci per cell: 8.4 DMSO, 19.3 veliparib, 58.7 talazoparib) and with IR (22.4 DMSO, 32.8 veliparib, 75.6 talazoparib). Finally, a dose of 0.2 mg/kg talazoparib in vivo led to statistically significant tumor growth inhibition in combination with IR but not as a single agent in three SCLC PDX models. PARP inhibition effectively sensitizes SCLC cell lines and PDXs to IR, and PARP trapping correlates with radiosensitization. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiation therapy in SCLC.

Talazoparib Is a Potent Radiosensitizer in Small Cell Lung Cancer Cell Lines and Xenografts.

Purpose: Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization.Experimental Design: Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in 6 SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models.Results: Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays and confirmed in 3 of 3 cell lines by CSAs. Concentrations of 200 nmol/L talazoparib and 1,600 nmol/L veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization. This observation further correlated with an increased number of double-stranded DNA breaks induced by talazoparib as compared with veliparib. Finally, a dose of 0.2 mg/kg talazoparib in vivo caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models.Conclusions: PARP inhibition effectively sensitizes SCLC cell lines and PDXs to IR, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiotherapy in SCLC. Clin Cancer Res; 24(20); 5143-52. ©2018 AACR.

Mechanistic Exploration of Cancer Stem Cell Marker Voltage-Dependent Calcium Channel α2δ1 Subunit-mediated Chemotherapy Resistance in Small-Cell Lung Cancer.

Purpose: Chemoresistance in small-cell lung cancer (SCLC) is reportedly attributed to the existence of resistant cancer stem cells (CSC). Studies involving CSC-specific markers and related mechanisms in SCLC remain limited. This study explored the role of the voltage-dependent calcium channel α2δ1 subunit as a CSC marker in chemoresistance of SCLC, and explored the potential mechanisms of α2δ1-mediated chemoresistance and strategies of overcoming the resistance.Experimental Design: α2δ1-positive cells were identified and isolated from SCLC cell lines and patient-derived xenograft (PDX) models, and CSC-like properties were subsequently verified. Transcriptome sequencing and Western blotting were carried out to identify pathways involved in α2δ1-mediated chemoresistance in SCLC. In addition, possible interventions to overcome α2δ1-mediated chemoresistance were examined.Results: Different proportions of α2δ1+ cells were identified in SCLC cell lines and PDX models. α2δ1+ cells exhibited CSC-like properties (self-renewal, tumorigenic, differentiation potential, and high expression of genes related to CSCs and drug resistance). Chemotherapy induced the enrichment of α2δ1+ cells instead of CD133+ cells in PDXs, and an increased proportion of α2δ1+ cells corresponded to increased chemoresistance. Activation and overexpression of ERK in the α2δ1-positive H1048 cell line was identified at the protein level. mAb 1B50-1 was observed to improve the efficacy of chemotherapy and delay relapse as maintenance therapy in PDX models.Conclusions: SCLC cells expressing α2δ1 demonstrated CSC-like properties, and may contribute to chemoresistance. ERK may play a key role in α2δ1-mediated chemoresistance. mAb 1B50-1 may serve as a potential anti-SCLC drug. Clin Cancer Res; 24(9); 2148-58. ©2018 AACR.

Noninvasive Interrogation of DLL3 Expression in Metastatic Small Cell Lung Cancer.

The Notch ligand DLL3 has emerged as a novel therapeutic target expressed in small cell lung cancer (SCLC) and high-grade neuroendocrine carcinomas. Rovalpituzumab teserine (Rova-T; SC16LD6.5) is a first-in-class DLL3-targeted antibody-drug conjugate with encouraging initial safety and efficacy profiles in SCLC in the clinic. Here we demonstrate that tumor expression of DLL3, although orders of magnitude lower in surface protein expression than typical oncology targets of immunoPET, can serve as an imaging biomarker for SCLC. We developed 89Zr-labeled SC16 antibody as a companion diagnostic agent to facilitate selection of patients for treatment with Rova-T based on a noninvasive interrogation of the in vivo status of DLL3 expression using PET imaging. Despite low cell-surface abundance of DLL3, immunoPET imaging with 89Zr-labeled SC16 antibody enabled delineation of subcutaneous and orthotopic SCLC tumor xenografts as well as distant organ metastases with high sensitivity. Uptake of the radiotracer in tumors was concordant with levels of DLL3 expression and, most notably, DLL3 immunoPET yielded rank-order correlation for response to SC16LD6.5 therapy in SCLC patient-derived xenograft models. Cancer Res; 77(14); 3931-41. ©2017 AACR.

Abstract B169: A mouse avatar tumor maintenance study identified a subset of SCLC patient-derived tumor xenograft models sensitive to the PARP inhibitor niraparib

Abstract Introduction Small cell lung cancer (SCLC) is an aggressive form of disease that accounts for approximately 15% of all lung cancers. To date, targeted therapies have not impacted the treatment paradigm, which is dominated by platinum-based regimens. Here we evaluate the potential of niraparib, a clinical stage poly-ADP-ribose polymerase 1 inhibitor, in a cohort of 31 SCLC patient-derived xenograft (PDX) models in mice. Methods For the initial screening study forty-two SCLC PDX models were inoculated subcutaneously into the rear flank of NOD-SCID mice. Thirty-one models were placed on study. For each model, one animal was treated with a dose of chemotherapy to mimic front line standard of care (SOC, cisplatin day 1; etoposide day 1- 3), and one animal was dosed with the same representative SOC regimen followed by a niraparib maintenance regimen (starting day 8, QDx48). Confirmatory efficacy studies were performed on six responsive models with n = 5 per group. For all efficacy studies, tumor and body weight measurements were taken three times per week. Whole exome sequencing was carried out on untreated tumor samples from six highly sensitive and four resistant models to identify biomarkers predictive of response. Sequencing was performed on DNA from fresh frozen tissue to a depth of approximately 140x mean target coverage. Results Both the SOC, and SOC plus niraparib maintenance regimens were well-tolerated with no signs of treatment-related toxicity or significant body weight loss. Robust tumor growth inhibition (TGI) was observed in 6 of 31 (19%) models. Importantly, responses were confirmed in 6 of 6 models that were repeated with cohorts of 5 animals per treatment regimen. All tumor models that exhibited sensitivity to niraparib were considered platinum/etoposide responsive based on an anti-tumor response to the initial cisplatin/etoposide treatment. Robust TGI was observed in 6 of the 20 (30%) tumor models that exhibited sensitivity to cisplatin/etoposide treatment. Whole exome sequencing of sensitive vs. resistant tumors identified mutations in genes that may be used to further enrich for tumors that would be sensitive to maintenance niraparib treatment after first line cisplatin/etoposide treatment. Conclusions Niraparib exhibited robust anti-cancer activity in 30% of cisplatin/etoposide sensitive SCLC PDX models challenged with a dosing regimen that mimics SOC followed by niraparib maintenance. These data provide support for the clinical development of niraparib in platinum-sensitive patients and suggest biomarkers that may be useful for additional patient enrichment strategies. Citation Format: Keith Mikule, Yan Wang, Yonhong Xiao, Jill Rocono, Thomas Broudy, Keith Wilcoxen. A mouse avatar tumor maintenance study identified a subset of SCLC patient-derived tumor xenograft models sensitive to the PARP inhibitor niraparib. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr B169.

Abstract A37: Talazoparib predictive biomarker analysis in human small cell lung cancer cells and PDX tumors

Abstract Background: Small cell lung cancer (SCLC) is an aggressive subtype of lung cancer, accounting for ∼15% of all lung cancer cases in US. Talazoparib (BMN 673) is a potent, specific PARP1/2 inhibitor that has demonstrated significant clinical activity in ovarian and breast cancer patients with deleterious germline BRCA1/2 mutations (ASCO 2014). Antitumor responses were also reported in SCLC patients treated with talazoparib (ASCO 2014). However, molecular determinants for SCLC response to talazoparib treatment have not been determined. Method: in vitro: 38 human SCLC cell lines were screened for their sensitivity towards single-agent treatment with talazoparib or cisplatin. Sensitive vs. resistant cell lines were categorized based on median GI50 of 38 cell lines (as measured by generational growth inhibition approach) and 90% experimental maximum inhibition. Bioinformatics analysis was carried out to search for genomic features associated with talazoparib sensitivity, using CCLE genomic profiling data. in vivo: 12 human SCLC patient-derived xenograft (PDX) tumor models were established in immunocompromised mice. These PDX models were treated with either vehicle or talazoparib, and tumor growth was monitored by standard methods. Untreated tumor samples were collected from mice for molecular analyses (Myriad HRD assay, Foundation Medicine gene mutation analysis, reverse-phase protein array (RPPA), and Western blotting) to survey for talazoparib sensitivity biomarkers. Result: The 38 SCLC lines showed a wide range of sensitivity to talazoparib (GI50 ranging from 2 nM to &amp;gt;2000 nM, with median GI50 = 56 nM) and cisplatin treatment (GI50 ranging from 10 nM to &amp;gt;10,000 nM). Sensitivity towards talazoparib and cisplatin are well correlated (Pearson r = 0.748). Differential gene expression analysis suggests sensitivity to talazoparib correlated well with high SLFN11 expression in SCLC lines (nominal p-value &amp;lt; 0.001). The in vitro sensitivity results were confirmed in several cell line-derived xenograft models. In the SCLC PDX tumor screen, 3 of 12 PDX models showed tumor regression during talazoparib treatment with one complete response; 3 of 12 PDX tumors exhibited stable disease (SD)-like responses, while the remainder were resistant to talazoparib treatment. Gene mutation analysis indicates that all 12 SCLC PDX tumors have TP53 and/or RB1 mutations as expected for SCLC, but a correlation between mutations in the homologous recombination DNA repair genes (e.g. BRCA1, BRCA2, ATM) and response to talazoparib was not established in these models. Furthermore, no apparent relationship was found between talazoparib response and the Myriad HRD score in these SCLC PDX models, with all HRD scores being below the cutoff score associated with response to platinum treatment in breast and ovarian cancer. Protein expression analysis of PDX tumors is currently underway, and data will be presented at the meeting. Citation Format: Ying Feng, Karen Yu, Robert Cardnell, Yuanbin (Kevin) Ru, Evelyn Wang, Jing Wang, Leonard E. Post, Lauren A. Byers, Yuqiao (Jerry) Shen. Talazoparib predictive biomarker analysis in human small cell lung cancer cells and PDX tumors. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr A37.