Dysregulation Of PI3K Pathway Research Articles

Selected Articles from This Issue

Abemaciclib is an oral, potent and selective CDK4 & 6 inhibitor, dosed on a continuous schedule and approved as monotherapy and in combination with either fulvestrant or an aromatase inhibitor for HR+, HER2− advanced breast cancer (ABC). ESR1 mutation and PI3K pathway dysregulation are associated with resistance to endocrine therapy, and treatment with CDK4 & 6 inhibitors has been hypothesized as a therapeutic strategy to overcome endocrine resistance. In this exploratory analysis, Tolaney and colleagues show in HR+, HER2− ABC, abemaciclib plus fulvestrant improved both PFS and OS, regardless of PIK3CA or ESR1 mutation status. Additionally, abemaciclib plus fulvestrant improved other endpoints, including TTC, CFS and PFS2, regardless of PIK3CA or ESR1 mutation status. These findings support further evaluation in suitably powered trials.Combined targeting of the lineage-specific master transcription factor, ETV1, and signaling factor, KIT, by the combination of KIT and MEK inhibitors, is synergistic in preclinical GIST models. Chi and colleagues report the results of a phase Ib clinical trial designed to both evaluate the safety of the combination of imatinib and binimetinib and to determine the recommended phase II dose (RP2D) and early efficacy signal of this drug combination in patients with refractory advanced KIT/PDGFRA-mutant and KIT/PDGFRA wild-type GIST including SDH-deficient GIST. The study demonstrated that the combination of imatinib/binimetinib was safe with manageable side effects and determined the RP2D. They observed durable pathological responses in a small cohort of SDH-deficient GIST patients in the phase Ib expansion at RP2D. The promising clinical activity of the combination treatment in SDH-deficient GIST observed is worthy of further clinical investigation.Cyclin-dependent kinase 4/6 inhibition may have synergistic anticancer activity when combined with taxane chemotherapy. To explore this combination in metastatic castration-resistant prostate cancer (mCRPC), de Kouchkovsky and colleagues conducted a phase Ib/IIa study of ribociclib plus docetaxel in mCRPC patients who had progressed on an androgen receptor signaling inhibitor (ARSI). With intermittent ribociclib dosing and prophylactic growth factor, the combination demonstrated an acceptable safety profile, achieved a 6-month radiographic progression-free survival (rPFS) rate of 65.8%, and a median rPFS of 8.1 months. These results compare favorably to outcomes seen with docetaxel monotherapy after ARSI therapy. Further prospective study is warranted.KRAS is the most commonly mutated driver oncogene in solid tumors, including non-small cell lung cancer (NSCLC), with mutations spanning codons 12, 13 and 61. To explore the role of different mutant KRAS isoforms in pre-clinical models and samples from patients, Ricciuti and colleagues developed an isogenic cell-based platform to compare the oncogenic properties and specific therapeutic actionability across the 6 most common KRAS mutant variants. In addition, by surveying a large institutional dataset totaling >3000 NSCLC they identified clinicopathologic and genomic characteristics which correlated with unique KRAS mutant isoforms. Together, these findings revealed that KRAS mutations are highly heterogenous in terms of biological outcome and genomic profiling, and that this heterogeneity can be exploited to unveil novel potentially actionable vulnerabilities for KRAS mutant NSCLC.

Abstract 327: The impact of PIK3CA/PTEN/AKT1 genes in advanced NSCLC patients with acquired EGFR-TKI resistance and clinical response to EGFR-TKI plus everolimus combination therapy

Abstract Background EGFR-TKIs have shown remarkable effect in non-small cell lung cancer (NSCLC) patients with sensitive EGFR mutations. Nevertheless, several mechanisms including activation of PI3K/AKT/mTOR pathway have been proved to generate acquired assistance to EGFR-TKIs. In this study, we investigated the genomic characteristics of PI3K pathway in NSCLC patients with acquired resistance to EGFR-TKIs and whether both targeting EGFR and mTOR could reverse resistance. Methods A total of 605 NSCLC cases who received prior TKI treatment were reviewed, in which 328 patients harboring EGFR-mutants were confirmed to have progressed on one or more TKI and finally enrolled. FFPE tumor or blood samples were collected at the onset of TKI resistance for NGS based panel assay (PIK3CA/PTEN/AKT1 genes and NSCLC driver genes are included). Six patients with co-mutations in EGFR and PI3K pathway who had been heavily treated and progressed on EGFR-TKI received EGFR-TKI plus mTOR inhibitor everolimus combination therapy. Results In a total of 328 patients, 294 (89.6%) of the patients were adenocarcinomas, 4(12.2%) were small cell lung cancer, while the rest were squamous carcinoma or NSCLC not otherwise specified (30, 9.2%). Forty nine (14.9%) patients with TKI resistant have genomic alterations in PI3K pathway. PIK3CA, PTEN and AKT1variations were detected in 31(9.5%), 18(5.5%) and 3(0.9%) of patients respectively. Three patients had both PIK3CA and PTEN mutations and one patient had co-mutation of PIK3CA/PTEN/AKT1. PIK3CA hotspot mutations of E545, H1047 and E542 accounted for 60.5% of PIK3CA mutations. Six patients were treated with everolimus (5mg) plus EGFR-TKI (2 patients with gefitinib, 250mg; 1 patient with afatinib, 30mg; 3 patients with osimertinib 80mg, daily) combination therapy. One (1/6, 16.7%) patient achieved partial response and the rest (5/6, 83.3%) achieved stable disease. The most common adverse events were dental ulcer (6/6), rash (2/6), pruritis (1/6) and diarrhea (1/6). One patient withdrew combination treatment due to grade 3 dental ulcer. Conclusions Our study revealed that PI3K pathway was activated in approximately 15% of EGFR-TKI resistant patients. Combination therapy of EGFR-TKIs and everolimus revealed limited antitumor activity in EGFR-TKI resistant NSCLC patients with dysregulation of PI3K pathway. Citation Format: Wenfeng Fang, Yihua Huang, Jiadi Gan, Yunpeng Yang, Yifen Wu, Jingbin Huang, Zhiyong Xu, Wenjing Wang, Li Zhang. The impact of PIK3CA/PTEN/AKT1 genes in advanced NSCLC patients with acquired EGFR-TKI resistance and clinical response to EGFR-TKI plus everolimus combination therapy [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 327.

A Precision B Cell-Targeted Therapeutic Approach to Autoimmunity Caused by Phosphatidylinositol 3-Kinase Pathway Dysregulation.

The inositol lipid phosphatases PTEN and SHIP-1 play a crucial role in maintaining B cell anergy and are reduced in expression in B cells from systemic lupus erythematosus and type 1 diabetes patients, consequent to aberrant regulation by miRNA-7 and 155. With an eye toward eventual use in precision medicine therapeutic approaches in autoimmunity, we explored the ability of p110δ inhibition to compensate for PI3K pathway dysregulation in mouse models of autoimmunity. Low dosages of the p110δ inhibitor idelalisib, which spare the ability to mount an immune response to exogenous immunogens, are able to block the development of autoimmunity driven by compromised PI3K pathway regulation resultant from acutely induced B cell-targeted haploinsufficiency of PTEN and SHIP-1. These conditions do not block autoimmunity driven by B cell loss of the regulatory tyrosine phosphatase SHP-1. Finally, we show that B cells in NOD mice express reduced PTEN, and low-dosage p110δ inhibitor therapy blocks disease progression in this model of type 1 diabetes. These studies may aid in the development of precision treatments that act by enforcing PI3K pathway regulation in patients carrying specific risk alleles.

Abstract 4687: The PI3K inhibitor GDC-0941 is synergistic with lapatinib, and mediates endocrine sensitivity in uterine papillary serous carcinoma

Abstract Objectives: Our objective is to determine the effect of PI3K activity in mediating ligand-independent estrogen signaling and endocrine sensitivity in Uterine Papillary Serous Carcinoma (UPSC). Methods: Drug effect on cell proliferation was calculated via Calcusyn in patient-derived UPSC cell lines ARK 1 and 2. PI3K mutation was analyzed after laser capture microdissection of tumor DNA in 7 consecutive patients with UPSC. Protein expression, via Western Blot, was correlated prospectively with clinical parameters. Results: Table 1 shows cells line baseline characteristics and IC50 to drugs. Fulvestrant, an ER antagonist, rendered the cells significantly more resistant to taxol in ARK1 and 2(p=0.035, 0.021 respectively). The concomitant decrease in pERS167 and pAKTS473 with Fulvestrant treatment is independent of baseline ER expression and PI3K mutation. In ARK2, a cell line that is ER-, disrupting AKT signaling via the PI3K inhibitor GDC-0941, or with the lapatinib is synergistic with Fulvestrant with Combination Index (CI)50 of 0.441 and 0.229, respectively. Independent of HER2 amplification or PI3K mutation, lapatinib and GDC-0941 exhibited synergistic cytotoxicity in both UPSC cell lines (CI50 of 0.577, ARK 1 and 0.233, ARK2). Finally, PI3K mutation and pAKTS473 expression was analyzed in 7 tumor samples. While none harbored PI3K mutation, patients who are chemotherapy resistant had significantly lower expression of baseline pAKTS473 in their tumor samples than those who are chemosensitive, similar to our cell line data. Conclusions: PI3K pathway dysregulation, either via upstream erbB amplification, or downstream constitutive activation of AKT, may be important in mediating endocrine and taxol sensitivity in UPSC. pAKTS473 may be an important biomarker of drug sensitivity. The combination of PI3K inhibitor and lapatinib is synergistic and warrant further therapeutic investigation. Baseline characteristics and drug sensitivities in UPSC cell linesARK1ARK2PI3KCA mutationfExon 9NoERα (WB)YesNopERα167 (WB)YesNopHER (WB)NoYesIC50 nM (mean ± STD)GDC-094193.1±5.9271±116.5LapatinibNo effect135.6±29.2FulvestrantNo effectNo effectTaxol4.6±1.97.8±5.6Cisplatin1103±65.72632.6±1797.9 Citation Format: Kelly S. Levano, Alicia Rodriguez-Gabin, Gary L. Goldberg, Susan B. Horwitz, June Y. Hou. The PI3K inhibitor GDC-0941 is synergistic with lapatinib, and mediates endocrine sensitivity in uterine papillary serous carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4687. doi:10.1158/1538-7445.AM2014-4687

PI3K pathway (PI3Kp) dysregulation and response to pan-PI3K/AKT/mTOR/dual PI3K-mTOR inhibitors (PI3Kpi) in metastatic breast cancer (MBC) patients (pts).

509 Background: The role of PI3Kp dysregulation as a predictor of sensitivity to PI3Kpi is unclear. We aimed to evaluate the efficacy of PI3Kpi in two cohorts of MBC pts with assessable PI3Kp status. Methods: MBC pts treated in ≥3rd line with PI3Kpi were reviewed. PI3Kp status: (a) No dysregulation: PIK3CA wt and PTEN normal; (b) PI3Kp dysregulation: PIK3CA mutation (PIK3CAmut) or PTEN low (HScore≤50). Cohort A: pts treated with single agent PI3Kpi. Cohort B: pts treated with PI3Kpi in combination with hormonal therapy (HT), chemotherapy (CT) and/or trastuzumab (T). Results: Out of 232 MBC pts screened for PI3Kp alterations from Sep09 to Sep11, 32 were treated with PI3Kpi. Cohort A (n=17): HR+/HER2- 88%, HER2+ 6%, triple negative 6%; median age 43, median MBC lines 4 (2-9); PIK3CAmut in 10/17 (58.8%; 6 exon9, 4 exon20), PTEN low 3/17 (17.6%), 1 pt both; PI3Kp dysregulation 12/17 pts. Cohort B (n=15): HR+/HER2- 40%, HER2+ 60%; median age 49, median MBC lines 4 (2-13); PIK3CAmut 3/13 assessable (23.1%; all exon20), PTEN low 6/15 (40%), 1 pt both; PI3Kp dysregulation 8/15 pts. Time to progression to PI3Kpi (TTP), overall survival from MBC diagnosis (OSMBC) and OS from PI3Kpi beginning (OSPI3Kpi), according to PIK3CA status and PI3Kp dysregulation, are shown. No differences were found according to PTEN status. Conclusions: These results suggest that the best outcomes with PI3Kpi in PIK3CAmut MBC pts occur when they are used in combination with HT/CT/T. Activity of non selective PI3Kpi used as single agents seems to be limited, making results from prospective trials with selective PI3Kα inhibitors and PI3Kpi in combinations eagerly awaited. [Table: see text]

A phase I safety and pharmacokinetic study of XL765 (SAR245409), a novel PI3K/TORC1/TORC2 inhibitor, in combination with temozolomide (TMZ) in patients (pts) with newly diagnosed malignant glioma.

3085 Background: PI3K pathway dysregulation has been implicated in resistance to TMZ in preclinical glioma models. XL765, a potent and selective inhibitor of class I PI3K isoforms and TORC1 and TORC2, has demonstrated dose-dependent target modulation in both tumor xenograft models and in normal brain tissue in preclinical studies. Methods: Pts with WHO grade III and IV astrocytic tumors who have received standard chemoradiation with TMZ followed by at least one cycle of maintenance TMZ (200 mg/m2/day × 5 q 28 days) are eligible. XL765 is dose escalated following a standard 3 + 3 design and administered in combination with a fixed dose of TMZ. Results: 18 pts have been treated with XL765 in combination with TMZ across 4 dose levels of XL765 (30, 40, 50, and 60 mg qd). The maximum administered dose (MAD) of XL765 is 60 mg for the qd schedule; 2 of 6 pts experienced DLTs. The most common (≥ 10%) treatment-related AEs were nausea, hyperglycemia, constipation, fatigue, thrombocytopenia, and skin disorders. Grade ≥ 3 treatment related AEs were observed in four pts: grade 3 brain edema and grade 4 thrombocytopenia (one pt, also reported as a DLT), grade 3 rash (one pt, also reported as a DLT), grade 3 thrombocytopenia (one pt), and grade 4 increased transaminases (one pt). Based on comparison with single agent data, no major PK interaction between XL765 and TMZ is evident. At the 30 and 40 mg qd XL765 dose levels, inhibition of PI3K pathway (pAKT-T308, pAKT-S473, and p4EBP1) signaling has been demonstrated in skin. Based on assessment of archival tumor material, the most common molecular alterations detected include MGMT promoter methylation, PTEN point mutations, and EGFR gene amplification. Of the first 18 pts enrolled, seven pts have remained on study for > 16 weeks, one of whom continued on study for 62 weeks. Conclusions: XL765 in combination with TMZ is generally well tolerated at doses up to 40 mg qd. There is no apparent PK interaction between XL765 and TMZ. MTD determinations for qd and bid schedules are ongoing. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Exelixis Exelixis Exelixis Exelixis, Genentech, Schering-Plough