Abstract 2070: Exploration of markers of synergistic lethality of PARP and PI3K-Akt-mTOR inhibitors in women's cancers

Abstract

Abstract Introduction: The objective was to identify molecular mechanisms and protein networks involved in synthetic lethality as well as mechanisms of adaptive changes to the combination of olaparib (O) combined with inhibitors of the PI3K-AKT axis. Methods: 110 patients with recurrent ovarian, endometrial, and triple negative breast cancer were treated with a combination of O and vistusertib (V) or capivasertib (C) (mTORC1/2 and AKT inhibitors, respectively). We have previously reported durable clinical efficacy of these combinations, regardless of BRCA status. Tumor samples were collected pre-treatment and 30 days post-treatment and reverse-phase protein array (RPPA) was performed. Baseline expression was assessed and change in expression was calculated. Bioinformatics and statistical methods were developed to assess activity of signaling pathways. Pathway scores were determined based on the expression of sets of proteins known to be involved in a specific pathway, including PI3K, RAS/RAF, and DNA damage repair. Association between protein expression and treatment efficacy was determined. Results: We analyzed a total of 55 paired samples from patients treated with O/V (n=25) and O/C (n=30). These included 20 endometrial (37% PR, 31.5% SD, 31.5% PD), 21 ovarian (10% PR, 55% SD, 35% PD) and 14 triple negative breast (15% PR, 23% SD, 62% PD) tumors. Response to O/V was associated with low pre-treatment mTOR pathway activity and led to altered immune activity based on decreased CD4 and PD1 expression. Resistance to O/V was associated with high pre-treatment cell proliferation (high CCNB1, CDK1 and PLK1 protein expression). In contrast, response to O/C was associated with adaptive responses indicated by decreased mTOR activity and induction of the DNA damage checkpoint (high phospho-CHK1, -WEE1 and -CDC2). Resistance was associated with high pre-treatment RTK activity levels (high phospho-HER3, -EGFR, -IGFR, -MET) and AKT-independent activation of mTOR in the on-treatment samples. Conclusion: Analysis of pre- and on-treatment samples from responders and non-responders to PARP and PI3K pathway combination therapy identified biomarkers of patients likely to benefit from therapy and helps to understand molecular mechanisms involved in response and resistance to these drug combinations. Citation Format: Marilyne Labrie, Zhenlin Ju, Jennifer K. Litton, Tae-Beom Kim, Sanghoon Lee, Ken Chen, Pamela T. Soliman, Michael Frumovitz, Larissa A. Meyer, Stacy Moulder, Amir A. Jazaeri, Karen H. Lu, Anil K. Sood, Robert L. Coleman, Gordon B. Mills, Shannon N. Westin. Exploration of markers of synergistic lethality of PARP and PI3K-Akt-mTOR inhibitors in women's cancers [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 2070.