Abstract A091: Targeting homologous recombination repair defects in lung cancer

Abstract

Abstract Non-Small Cell Lung Cancer (NSCLC) is the leading cause of cancer related mortality worldwide, and accounts for 80-85% of all lung cancer diagnoses. While targeted therapies against epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) fusions have proven to be effective for the treatment of NSCLC, only a fraction of NSCLC patients (i.e. <20%) benefit from these targeted agents. Although immunotherapy approaches, specifically PD-1:PD-L1 blockade, appear to be more broadly efficacious, there are still a substantial proportion of patients who may not benefit from these treatments. To investigate the potential of targeting the DNA Damage Response (DDR) pathway in lung cancer, as an alternative therapeutic approach for these patients we sought to identify whether functionally relevant HRR (Homologous Recombination Repair)-defects could be synthetically lethal with niraparib monotherapy in NSCLC PDX models. Approximately 3% of lung cancers harbor mutations in ATM (i.e. 3.5% in lung adenocarcinomas & 1.4% in lung squamous cell carcinoma), which is involved in HRR as well as multiple other DNA repair and checkpoint functions, but the functional consequences of this alteration remain to be established. Studies in the past few years have demonstrated the potential of targeting the DDR pathway as a promising therapeutic strategy for lung cancer, i.e. in small cell lung cancer (SCLC) where overall response rates to immune checkpoint blockade remain poor. In addition, inhibitors targeting DDR proteins have shown promise in preclinical models of lung cancer, and are under clinical investigation as single agents and in combination with other targeted and immunotherapy agents. In this study, we have evaluated niraparib sensitivity in 57 NSCLC PDX models containing both BRCA and non-BRCA HRR mutations (n=17) as well as HRR WT models (n=40). This analysis demonstrated that niraparib sensitive models include both HRR mutant and HRR WT lung tumors (TGI > 70%). Amongst the PDX models containing a biallelic HRR mutation (ATM, BAP1, RAD51D & XRCC2), only ATM biallelic mutant models were sensitive to niraparib (2 out of 6). Furthermore, none of the of nine monoallelic mutant models (ATM, ATR, BRCA1/2, RAD50 & RAD52) were sensitive to niraparib. Surprisingly, 7.5% (3 out of 40) of the HRR WT PDX models were sensitive to niraparib. Further analysis is required to elucidate the molecular mechanisms driving niraparib sensitivity in HRR WT NSCLC. Citation Format: Asli Muvaffak, Yinghui Zhou, Bin Feng, Sarah Wang, Jing Ju Wang, Sridhar Ramaswamy, Kevin G Coleman. Targeting homologous recombination repair defects in lung cancer [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 A091. doi:10.1158/1535-7163.TARG-19-A091