Oncogene Addiction Research Articles

Atezolizumab with or without bevacizumab and platinum-pemetrexed in patients with stage IIIB/IV non-squamous non-small cell lung cancer with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies: A multicentre phase II open-label non-randomised study GFPC 06-2018

BackgroundPrevious reports showed limited efficacy of immune checkpoint inhibitors as single-agent treatment for non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation or ALK/ROS1 fusion. We aimed at evaluating the efficacy and safety of immune checkpoint inhibitor combined with chemotherapy and bevacizumab (when eligible) in this patient subgroup. MethodsWe conducted a French national open-label multicentre non-randomised non-comparative phase II study in patients with stage IIIB/IV NSCLC, oncogenic addiction (EGFR mutation or ALK/ROS1 fusion), with disease progression after tyrosine kinase inhibitor and no prior chemotherapy. Patients received platinum, pemetrexed, atezolizumab, bevacizumab (PPAB cohort) or, if not eligible to bevacizumab, platinum–pemetrexed–atezolizumab (PPA cohort). The primary end-point was the objective response rate (RECIST v1.1) after 12 weeks, evaluated by blind independent central review. Results71 patients were included in PPAB cohort and 78 in PPA cohort (mean age, 60.4/66.1 years; women 69.0%/51.3%; EGFR mutation, 87.3%/89.7%; ALK rearrangement, 12.7%/5.1%; ROS1 fusion, 0%/6.4%, respectively). After 12 weeks, objective response rate was 58.2% (90% confidence interval [CI], 47.4–68.4) in PPAB cohort and 46.5% (90% CI, 36.3–56.9) in PPA cohort. Median progression-free survival and overall survival were 7.3 (95% CI 6.9–9.0) months and 17.2 (95% CI 13.7–NA) months in PPAB cohort and 7.2 (95% CI 5.7–9.2) months and 16.8 (95% CI 13.5–NA) months in PPA cohort, respectively. Grade 3–4 adverse events occurred in 69.1% of patients in PPAB cohort and 51.4% in PPA cohort; Grade 3–4 atezolizumab-related adverse events occurred in 27.9% and 15.3%, respectively. ConclusionCombination approach with atezolizumab with or without bevacizumab and platinum-pemetrexed achieved promising activity in metastatic EGFR-mutated or ALK/ROS1-rearranged NSCLC after tyrosine kinase inhibitor failure, with acceptable safety profile.

Metabolism in Hematopoiesis and Its Malignancy.

Hematopoietic stem cells (HSCs) are multipotent stem cells that can self-renew and generate all blood cells of different lineages. The system is under tight control in order to maintain a precise equilibrium of the HSC pool and the effective production of mature blood cells to support various biological activities. Cell metabolism can regulate different molecular activities, such as epigenetic modification and cell cycle regulation, and subsequently affects the function and maintenance of HSC. Upon malignant transformation, oncogenic drivers in malignant hematopoietic cells can remodel the metabolic pathways for supporting the oncogenic growth. The dysregulation of metabolism results in oncogene addiction, implying the development of malignancy-specific metabolism-targeted therapy. In this chapter, we will discuss the significance of different metabolic pathways in hematopoiesis, specifically, the distinctive metabolic dependency in hematopoietic malignancies and potential metabolic therapy.

Inducible lncRNA transgenic mice reveal continual role of HOTAIR in promoting breast cancer metastasis.

HOTAIR is a 2.2-kb long noncoding RNA (lncRNA) whose dysregulation has been linked to oncogenesis, defects in pattern formation during early development, and irregularities during the process of epithelial-to-mesenchymal transition (EMT). However, the oncogenic transformation determined by HOTAIR in vivo and its impact on chromatin dynamics are incompletely understood. Here, we generate a transgenic mouse model with doxycycline-inducible expression of human HOTAIR in the context of the MMTV-PyMT breast cancer-prone background to systematically interrogate the cellular mechanisms by which human HOTAIR lncRNA acts to promote breast cancer progression. We show that sustained high levels of HOTAIR over time increased breast metastatic capacity and invasiveness in breast cancer cells, promoting migration and subsequent metastasis to the lung. Subsequent withdrawal of HOTAIR overexpression reverted the metastatic phenotype, indicating oncogenic lncRNA addiction. Furthermore, HOTAIR overexpression altered both the cellular transcriptome and chromatin accessibility landscape of multiple metastasis-associated genes and promoted EMT. These alterations are abrogated within several cell cycles after HOTAIR expression is reverted to basal levels, indicating an erasable lncRNA-associated epigenetic memory. These results suggest that a continual role for HOTAIR in programming a metastatic gene regulatory program. Targeting HOTAIR lncRNA may potentially serve as a therapeutic strategy to ameliorate breast cancer progression.

Exploring the Dynamic Crosstalk between the Immune System and Genetics in Gastrointestinal Stromal Tumors

Gastrointestinal Stromal Tumors (GISTs) represent a paradigmatic model of oncogene addiction. Despite the well-known impact of the mutational status on clinical outcomes, we need to expand our knowledge to other factors that influence behavior heterogeneity in GIST patients. A growing body of studies has revealed that the tumor microenvironment (TME), mostly populated by tumor-associated macrophages (TAMs) and lymphocytes (TILs), and stromal differentiation (SD) have a significant impact on prognosis and response to treatment. Interestingly, even though the current knowledge of the role of immune response in this setting is still limited, recent pre-clinical and clinical data have highlighted the relevance of the TME in GISTs, with possible implications for clinical practice in the near future. Moreover, the expression of immune checkpoints, such as PD-L1, PD-1, and CTLA-4, and their relationship to the clinical phenotype in GIST are emerging as potential prognostic biomarkers. Looking forward, these variables related to the underlying tumoral microenvironment in GIST, though limited to still-ongoing trials, might lead to the potential use of immunotherapy, alone or in combination with targeted therapy, in advanced TKI-refractory GISTs. This review aims to deepen understanding of the potential link between mutational status and the immune microenvironment in GIST.

An oncogene addiction phosphorylation signature and its derived scores inform tumor responsiveness to targeted therapies

PurposeOncogene addiction provides important therapeutic opportunities for precision oncology treatment strategies. To date the cellular circuitries associated with driving oncoproteins, which eventually establish the phenotypic manifestation of oncogene addiction, remain largely unexplored. Data suggest the DNA damage response (DDR) as a central signaling network that intersects with pathways associated with deregulated addicting oncoproteins with kinase activity in cancer cells.ExperimentalDesignWe employed a targeted mass spectrometry approach to systematically explore alterations in 116 phosphosites related to oncogene signaling and its intersection with the DDR following inhibition of the addicting oncogene alone or in combination with irradiation in MET-, EGFR-, ALK- or BRAF (V600)-positive cancer models. An NSCLC tissue pipeline combining patient-derived xenografts (PDXs) and ex vivo patient organotypic cultures has been established for treatment responsiveness assessment.ResultsWe identified an ‘oncogene addiction phosphorylation signature’ (OAPS) consisting of 8 protein phosphorylations (ACLY S455, IF4B S422, IF4G1 S1231, LIMA1 S490, MYCN S62, NCBP1 S22, P3C2A S259 and TERF2 S365) that are significantly suppressed upon targeted oncogene inhibition solely in addicted cell line models and patient tissues. We show that the OAPS is present in patient tissues and the OAPS-derived score strongly correlates with the ex vivo responses to targeted treatments.ConclusionsWe propose a score derived from OAPS as a quantitative measure to evaluate oncogene addiction of cancer cell samples. This work underlines the importance of protein phosphorylation assessment for patient stratification in precision oncology and corresponding identification of tumor subtypes sensitive to inhibition of a particular oncogene.

Phosphoproteomic analysis of neoadjuvant breast cancer suggests that increased sensitivity to paclitaxel is driven by CDK4 and filamin A

Precision oncology research is challenging outside the contexts of oncogenic addiction and/or targeted therapies. We previously showed that phosphoproteomics is a powerful approach to reveal patient subsets of interest characterized by the activity of a few kinases where the underlying genomics is complex. Here, we conduct a phosphoproteomic screening of samples from HER2-negative female breast cancer receiving neoadjuvant paclitaxel (N = 130), aiming to find candidate biomarkers of paclitaxel sensitivity. Filtering 11 candidate biomarkers through 2 independent patient sets (N = 218) allowed the identification of a subgroup of patients characterized by high levels of CDK4 and filamin-A who had a 90% chance of achieving a pCR in response to paclitaxel. Mechanistically, CDK4 regulates filamin-A transcription, which in turn forms a complex with tubulin and CLIP-170, which elicits increased binding of paclitaxel to microtubules, microtubule acetylation and stabilization, and mitotic catastrophe. Thus, phosphoproteomics allows the identification of explainable factors for predicting response to paclitaxel.

Expression Ratios of the Antiapoptotic BCL2 Family Members Dictate the Selective Addiction of Kaposi's Sarcoma-Associated Herpesvirus-Transformed Primary Effusion Lymphoma Cell Lines to MCL1.

Kaposi's sarcoma-associated herpesvirus (KSHV) causes several malignancies in people living with HIV, including primary effusion lymphoma (PEL). PEL cell lines exhibit oncogene addictions to both viral and cellular genes. Using CRISPR screens, we previously identified cellular oncogene addictions in PEL cell lines, including MCL1. MCL1 is a member of the BCL2 family, which functions to prevent intrinsic apoptosis and has been implicated in several cancers. Despite the overlapping functions of the BCL2 family members, PEL cells are dependent only on MCL1, suggesting that MCL1 may have nonredundant functions. To investigate why PEL cells exhibit selective addiction to MCL1, we inactivated the intrinsic apoptosis pathway by engineering BAX/BAK1 double knockout cells. In this context, PEL cells become resistant to MCL1 knockdown or MCL1 inactivation by the MCL1 inhibitor S63845, indicating that the main function of MCL1 in PEL cells is to prevent BAX/BAK1-mediated apoptosis. The selective requirement to MCL1 is due to MCL1 being expressed in excess over the BCL2 family. Ectopic expression of several BCL2 family proteins, as well as the KSHV BCL2 homolog, significantly decreased basal caspase 3/7 activity and buffered against staurosporine-induced apoptosis. Finally, overexpressed BCL2 family members can functionally substitute for MCL1, when it is inhibited by S63845. Together, our data indicate that the expression levels of the BCL2 family likely explain why PEL tumor cells are highly addicted to MCL1. Importantly, our results suggest that caution should be taken when considering MCL1 inhibitors as a monotherapy regimen for PEL because resistance can develop easily. IMPORTANCE Primary effusion lymphoma (PEL) is caused by Kaposi's sarcoma-associated herpesvirus. We showed previously that PEL cell lines require the antiapoptotic protein MCL1 for survival but not the other BCL2 family proteins. This selective dependence on MCL1 is unexpected as the BCL2 family functions similarly in preventing intrinsic apoptosis. Recently, new roles for MCL1 not shared with the BCL2 family have emerged. Here, we show that noncanonical functions of MCL1 are unlikely essential. Instead, MCL1 functions mainly to prevent apoptosis. The specific requirement to MCL1 is due to MCL1 being expressed in excess over the BCL2 family. Consistent with this model, shifting these expression ratios changes the requirement away from MCL1 and toward the dominant BCL2 family gene. Together, our results indicate that although MCL1 is an attractive chemotherapeutic target to treat PEL, careful consideration must be taken, as resistance to MCL1-specific inhibitors easily develops through BCL2 family overexpression.

HER2 mRNA Levels, Estrogen Receptor Activity and Susceptibility to Trastuzumab in Primary Breast Cancer.

While the results thus far demonstrate the clinical benefit of trastuzumab in breast cancer (BC), some patients do not respond to this drug. HER2 mRNA, alone or combined with other genes/biomarkers, has been proven to be a powerful predictive marker in several studies. Here, we provide evidence of the association between HER2 mRNA levels and the response to anti-HER2 treatment in HER2-positive BC patients treated with adjuvant trastuzumab and show that this association is independent of estrogen receptor (ER) tumor positivity. While HER2 mRNA expression was significantly correlated with HER2 protein levels in ER-negative tumors, no correlation was found in ER-positive tumors, and HER2 protein expression was not associated with relapse risk. Correlation analyses in the ER-positive subset identified ER activity as the pathway inversely associated with HER2 mRNA. Associations between HER2 levels and oncogene addiction, as well as between HER2 activation and trastuzumab sensitivity, were also observed in vitro in HER2-positive BC cell lines. In ER-positive but not ER-negative BC cells, HER2 transcription was increased by reducing ligand-dependent ER activity or inducing ER degradation. Accordingly, HER2 mRNA levels in patients were found to be inversely correlated with blood levels of estradiol, the natural ligand of ER that induces ER activation. Moreover, low estradiol levels were associated with a lower risk of relapse in HER2-positive BC patients treated with adjuvant trastuzumab. Overall, we found that HER2 mRNA levels, but not protein levels, indicate the HER2 dependency of tumor cells and low estrogen-dependent ER activity in HER2-positive tumors.

Uncovering Ethnic Genomic Disparities Associated with Inferior Outcome in African Americans Diagnosed with Acute Myelogenous Leukemia

Background: African Americans (AA) have higher cancer-associated mortality than other ethnicities. AA with AML exhibit inferior overall survival (OS) to non-AA subgroups (OS=162 d vs 709 d, respectively, p=0.0001, HR=7.8) Fig 1A. In other cancers, higher genomic instability (GI) and differential oncogenic addiction contribute to AA worse outcomes; however, in AML, genetic causes of inferior outcomes are uncharacterized. In this study, we seek to investigate differential AML mut and other factors that contribute to inferior AA OS. Methods: After IRB approval, 92/250 (36.8%) available AML patients (pt) had next generation sequencing (NGS) data and were included. Mut frequencies were annotated by ethnicity [White (W) vs AA vs Hispanic (H) vs Asians (A)] and prioritized by European Leukemia Network (ELN) 2017 classification. Numeric chromosomic alterations (NCA) were extracted from metaphase karyotyping at diagnosis. Deleteriousness of mutations to protein function was calculated with sorting intolerant from tolerant (SIFT) prediction method. Chi-square and t-test evaluated differences in categorical and continuous variables respectively. Logistic binary regression was used to detect predictors for racial induced survival. SAS software was used. Results: Whites (W), AA, Hispanics (H) and Asians (A) represented 57/91 (62%), 14/91 (15%), 20/91 and (22%), 5/91 (5.4%) of the cohort, respectively. Median age was 63 (W) , 57.5 (AA) , 53 (H), 62 (A), p=NS. 60/92 (65%) were male. Median number of mut were 2.04 (W), 1.8 (AA), 2.2 (H) and 1.8 (A), p=NS. Distribution for adverse ELN-2017 defects were equivalent among AA vs non-AA except RUNX1, p=0.05. Lack of favorable mut was observed among AA. Only AA demonstrated CUX1, previously associated with DNA repair defects, and FBXW7 mut. A non-significant trend for higher NCA in AA (2.7 [W], 6.4 [AA], 3 [H] and 0.8 [A], p=0.09) was observed. Age correlated with NCA and number of mut in AML genome, p=0.02 and p=0.004. Interestingly, correlation effect was mostly driven only by AA, p=0.02 and p=0.003, respectively. SIFT score was 0.01 (W), 0.09 (AA), 0.02 (H), and 0.01 (A). These SIFT results suggest that AA mut are functionally tolerated. After adjusting for multiple factors, only canonical ELN-2017 mut, p=0.02 (OR 0.37, CI 0.16-0.8), and AA race, p=0.005 (OR 0.25, CI 0.1-0.67) increased risk of death (c-statistics=0.66) Fig.1B. Conclusions: In AA, frequency of Adverse ELN-2017 mut is similar to other races, but favorable mutations were lacking. NCA and number of AML genome mut strongly correlate with aging in AA, but not other ethnic groups. Surprisingly, SIFT score failed to demonstrate functional deleteriousness for AA mut, which suggests alternative genomic defects as a culprit for poor outcome. Acknowledging the small number of mut in our cohort, our study advances our understanding of racial disparity in AML survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Liquid Biopsy and Immuno-Oncology for Advanced Nonsmall Cell Lung Cancer.

In the last decade, immune checkpoint inhibitors have revolutionized the treatment of metastatic nonsmall cell lung cancer without oncogenic addiction. Currently, programmed death ligand 1 (PD-L1) status, assessed in tissue biopsy samples, is the only test for guiding the prescription of these therapies in clinical practice. However, obtaining tumor tissue from patients with lung cancer is not always feasible and PD-L1 positivity is not a guarantee of immunotherapy efficacy. In this context, liquid biopsy, represented by several circulating biomarkers that reflect the tumor characteristics, is emerging as an interesting alternative approach. We describe the main blood biomarkers evaluated in patients with metastatic nonsmall cell lung cancer before/during immune checkpoint inhibitor treatment, with a focus on circulating cell-free DNA, circulating tumor DNA (ctDNA), blood tumor mutational burden, and circulating tumor cells (CTCs). Monitoring of ctDNA and CTCs during immunotherapy may be a promising tool to help clinicians in therapeutic decision-making.

Oncogenic Addiction of Fibrolamellar Hepatocellular Carcinoma to the Fusion Kinase DNAJB1-PRKACA.

Gene fusions are drivers of many pediatric tumors. In fibrolamellar hepatocellular carcinoma (FLC), a fusion of DNAJB1 and PRKACA is the dominant recurrent mutation. Expression of the DNAJB1-PRKACA fusion gene in mice results in a tumor that recapitulates FLC. However, it is not known whether transient expression of DNAJB1-PRKACA is sufficient only to trigger tumor formation or whether ongoing expression is necessary for maintenance and progression. We screened short hairpin RNAs (shRNA) tiled over the fusion junction and identified several potent and specific candidates in vitro and two independent FLC patient-derived xenografts (PDX). We show that continued DNAJB1-PRKACA expression is not only required for continued tumor growth, but additionally its inhibition results in cell death. Inhibition of DNAJB1-PRKACA by an inducible shRNA in cells of PDX of FLC resulted in cell death in vitro. Induction of the shRNA inhibits FLC tumors growing in mice with no effect on xenografts from a hepatocellular carcinoma cell line engineered to express DNAJB1-PRKACA. Our results validate DNAJB1-PRKACA as the oncogene in FLC and demonstrate both a continued requirement for the oncogene for tumor growth as well as an oncogenic addiction that can be exploited for targeted therapies. We anticipate our approach will be useful for investigations of other fusion genes in pediatric cancers and spur development of precision therapies.

Non-small-cell lung cancer: how to manage ALK-, ROS1- and NTRK-rearranged disease.

Oncogene addiction in non-small-cell lung cancer (NSCLC) has profound diagnostic and therapeutic implications. ALK, ROS1 and NTRK rearrangements are found in about 2–7%, 1–2% and 0.2% of unselected NSCLC samples, respectively; however, their frequency is markedly higher in younger and never-smoker patients with adenocarcinoma histology. Moreover, ALK, ROS1 and NTRK rearrangements are often mutually exclusive with other known driver alterations in NSCLC. Due to such a low frequency, diagnostic screening with accurate and inexpensive techniques such as immunohistochemistry is useful to identify positive cases; however, confirmation with fluorescent in situ hybridization or next-generation sequencing is often required due to higher specificity. In ALK-rearranged NSCLC, sequential treatment with second-generation and third-generation tyrosine kinase inhibitors leads to long-lasting disease control with most patients surviving beyond 5 years with metastatic disease. In ROS1-rearranged NSCLC, first-line treatment with crizotinib or entrectinib and subsequent treatment with lorlatinib at disease progression leads to similar results in patients with metastatic disease. NTRK1–3 fusions are extremely rare in unselected NSCLC. However, treatment with TRK inhibitors yields high response rates and durable disease control in most patients; diagnostic screening through multigene DNA/RNA-based next-generation sequencing testing is therefore crucial to identify positive cases.This article is part of the Treatment of advanced non-small-cell lung cancer: one size does not fit all Special Issue: https://www.drugsincontext.com/special_issues/treatment-of-advanced-non-small-cell-lung-cancer-one-size-does-not-fit-all/

Oncogenèse pulmonaire et bases biologiques des traitements ciblés

Lung carcinogenesis results from a multi-step process involving the accumulation of several molecular abnormalities linked, in smokers, to the interaction between the DNA of the epithelial cells of the respiratory system and the carcinogens of tobacco smoke. In non-smokers, the number of molecular abnormalities is lower, but it is the acquisition of a main molecular alteration (mutation or translocation) that makes the cell dependent for its survival on this alteration, either an “oncogenic addiction”. This main anomaly is most often a so-called “driver” mutation, activating an oncogene, a gene whose product promotes uncontrolled proliferation of the tumor cell. Patients with lung cancer harboring an oncogenic driver may be eligible for treatments specifically targeting this driver, treatments which have considerably improved their survival. However, when subjected to such treatments, tumor cells inevitably end up developing resistance mechanisms, which must then be identified in order to be able to adapt the therapeutic management of patients. This review of the literature aims to recall the main mechanisms of pulmonary carcinogenesis in order to understand what today constitutes the basis of the targeted treatments offered to patients with lung cancer according to the molecular abnormalities of their tumor, but also to understand why, these tumors will find a way to resist these targeted treatments and what strategies must be put in place to monitor the evolution of both the patient and his tumor, and adapt their therapeutic care in response to these changes.1877-1203/© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

Les nouveautés en immunothérapie : nouvelles cibles, rationnel et données précoces dans les cancers broncho-pulmonaires non à petites cellules

Therapeutic strategies with anti-PD-(L)1 antibodies are now well established in patients with nonsmall-cell lung cancer (NSCLC) without oncogenic addiction. The benefit of immunotherapy, sometimes leading to healing, remains restricted to “hot” tumors characterized by an inflammatory tumor micro-environment. Consequently, there is a need to develop new therapeutics improving the cytotoxic T cell activity. Antibodies targeting co-stimulatory or co-inhibitory receptors are evaluated in combination with anti-PD-(L)1 antibodies. Other approaches include anti-cancer vaccines or oncolytic virus. Overall, the goal is to effectively redirected the immune system against the tumor. This could be achieved and optimized by the identification of predictive biomarkers specific to the tumor and the patient for new individual therapeutic proposals.1877-1203/© 2022 SPLF. Published by Elsevier Masson SAS. All rights reserved.

208 (PB088) - Regulation of oncogenic transcription and tumor growth in pediatric cancers by the CDK9 inhibitor KB-0742

Background: Disruption of transcriptional regulatory networks that drive normal cellular differentiation and development can result in oncogenic transformation and transcriptional addiction. Many pediatric sarcomas are defined by/harbor oncogenic fusion proteins, resulting from chromosomal translocations such as the EWSR1 gene fused to an ETS family transcription factor (TF) gene (FLI1 or ERG) in Ewing sarcoma (ES), or PAX3/PAX7 and FOXO1 translocations in alveolar rhabdomyosarcoma (ARMS). In neuroblastoma, MYCN, a member of the MYC family of TFs, is often amplified and localizes to super enhancer regions, where it rewires lineage-specific transcriptional programs driving oncogenesis.

1016P GFPC 06-2018: A multicentre phase II, open-label, non-randomized study evaluating platinum-pemetrexed-atezolizumab (+/- bevacizumab) for patients with stage IIIB/IV non-squamous NSCLC with EGFR mutation, ALK rearrangement or ROS1 fusion progressing after targeted therapies

For patients (pts) with stage IIIB/IV NSCLC without oncogenic addiction (OA), immuno-checkpoint inhibitors (ICI) have emerged as a standard first-line treatment. Literature suggests a lower efficacy of ICI as single treatment in pts with OA, notably EGFR mutation or ALK/ROS1 rearrangement. Assuming adding chemotherapy to immunotherapy (CT-IO) may improve the management of pts with OA, we implemented a trial to assess the efficacy of this combination in this setting. We conducted a national, open, multicentre, non-randomized Phase II Study with two parallel cohorts: A (Platinum-Pemetrexed-Atezolizumab-Bevacizumab) and B (Platinum-Pemetrexed-Atezolizumab). Main eligibility criteria were: stage IIIB/IV NSCLC with EGFR mutation or ALK/ROS1 rearrangement progression after ≥1 targeted therapy and no prior chemotherapy and eligible for Bevacizumab (A). The primary endpoint was objective response rate (ORR) after 4 cycles (RECIST 1.1) evaluated by masked, independent central review. The secondary endpoints were PFS, OS and safety profile. For cohort A, an ORR of 35% (p0) was undesirable (and p1=50% expected). For cohort B, p0=30% and p1=45%. 149 pts were included (71 in A, 78 in B): for A/B respectively, mean age, 60.4/66.1 years; men 31/49%; alteration for EGFR 87/90%, ALK 13/5%, ROS1 0/6%. ORR was 58.2% (90% CI 47.4-68.4%, p<0.01) in A and 46.5% (90% CI 36.3-56.8%, p<0.01) in B. Disease control rate at 12 weeks was 89.6% (A) and 81.7% (B). Median PFS and OS were respectively 7.3 months (95% CI 6.9- 9.0), 17.2 months (95% CI 13.7-NA) in A and 7.2 months (95% CI 5.7-9.2), 16.8 months (95% CI 13.5-NA) in B. Grade 3-4 adverse events (AE) occurred in 69.1/51.4% (A/B). Severe immune-related AE occurred in 27.9/15.3% (A/B). No toxicity-related death was observed. Combination approach of Platinum-Pemetrexed-Atezolizumab-Bevacizumab or Platinum-Pemetrexed-Atezolizumab achieved promising efficacy in metastatic EGFR/ALK mutated NSCLC after TKI failure, with acceptable tolerance profile.

Abstract IA16: Trial enrichment and proof of concept studies

Abstract Identification of oncogene addiction loops has provided new therapeutic targets in oncology. Selective targeting of the ABL-BCR fusion in patients with chronic lymphocytic leukemia using imatinib was a major clinical breakthrough. Similar approaches in other solid tumors led to the approval of additional biomarker-driver molecular therapies (e.g., vemurafenib in BRAF mutated melanoma). Success of this approach was contingent on the identification of biomarkers that could help identify patients most likely to respond to these therapies. This spurred efforts to implement clinical trials able to detect efficacy in specific patient populations, specifically those enriched in the biomarker under evaluation. This has also been applied in hepatocellular carcinoma with mixed results. Approval of ramucirumab in patient with elevated AFP is the first example of successful trial enrichment, while tivantinib is paradigmatic of a negative biomarker enrichment trial. Lack of recurrent druggable mutations makes biomarker-driven clinical trials in HCC more difficult, which underscores the need for predictive biomarkers of immune therapies. Citation Format: Augusto Villanueva-Rodriguez. Trial enrichment and proof of concept studies [abstract]. In: Proceedings of the AACR Special Conference: Advances in the Pathogenesis and Molecular Therapies of Liver Cancer; 2022 May 5-8; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2022;28(17_Suppl):Abstract nr IA16.

Multiomics characterization implicates PTK7 in ovarian cancer EMT and cell plasticity and offers strategies for therapeutic intervention

Most patients with ovarian cancer (OC) are diagnosed at a late stage when there are very few therapeutic options and a poor prognosis. This is due to the lack of clearly defined underlying mechanisms or an oncogenic addiction that can be targeted pharmacologically, unlike other types of cancer. Here, we identified protein tyrosine kinase 7 (PTK7) as a potential new therapeutic target in OC following a multiomics approach using genetic and pharmacological interventions. We performed proteomics analyses upon PTK7 knockdown in OC cells and identified novel downstream effectors such as synuclein-γ (SNCG), SALL2, and PP1γ, and these findings were corroborated in ex vivo primary samples using PTK7 monoclonal antibody cofetuzumab. Our phosphoproteomics analyses demonstrated that PTK7 modulates cell adhesion and Rho-GTPase signaling to sustain epithelial-mesenchymal transition (EMT) and cell plasticity, which was confirmed by high-content image analysis of 3D models. Furthermore, using high-throughput drug sensitivity testing (525 drugs) we show that targeting PTK7 exhibited synergistic activity with chemotherapeutic agent paclitaxel, CHK1/2 inhibitor prexasertib, and PLK1 inhibitor GSK461364, among others, in OC cells and ex vivo primary samples. Taken together, our study provides unique insight into the function of PTK7, which helps to define its role in mediating aberrant Wnt signaling in ovarian cancer.

Proliferation and Self-Renewal Are Differentially Sensitive to NRASG12V Oncogene Levels in an Acute Myeloid Leukemia Cell Line.

Different levels of activated NRAS may exert distinct effects on proliferation and self-renewal.

Decreased DNA Damage and Improved p53 Specificity of RITA Analogs.

Reactivation of p53 tumor-suppressor function by small molecules is an attractive strategy to defeat cancer. A potent p53-reactivating molecule RITA, which triggers p53-dependent apoptosis in human tumor cells in vitro and in vivo, exhibits p53-independent cytotoxicity due to modifications by detoxification enzyme Sulfotransferase 1A1 (SULT1A1), producing a reactive carbocation. Several synthetic modifications to RITA's heterocyclic scaffold lead to higher energy barriers for carbocation formation. In this study, we addressed the question whether RITA analogs NSC777196 and NSC782846 can induce p53-dependent apoptosis without SULT1A1-dependent DNA damage. We found that RITA analog NSC782846, but not NSC777196, induced p53-regulated genes, targeted oncogene addiction, and killed cancer cells upon p53 reactivation, but without induction of DNA damage and inhibition RNA pol II. Our results might demonstrate a method for designing more specific and potent RITA analogs to accelerate translation of p53-targeting compounds from laboratory bench to clinic.