Abstract 4185: LP-184, a molecule with nanomolar potency, exhibits strong activity in lung cancers with KEAP1 and KRAS mutations

Abstract

Abstract As many as 40 percent of non-small cell lung cancers (NSCLC) either lack actionable targets for implementing targeted therapy and using immune-oncology agents, or progress following targeted therapy. Patients with such tumors depend on DNA damaging/alkylating agents. Very few available agents have nanomolar potency, with the majority being weakly cytotoxic (IC50> 20µM). Cisplatin based therapies also associate with high rates of drug resistance development, resulting from mutations such as those that affect NRF2 pathway. Newer drugs that will be more potent and remain efficacious in NSCLC with such mutations could lead to better alternate therapies. LP-184, currently in preclinical development, demonstrates highly potent anticancer activity in the NCI-60 cell line panel, with NSCLC emerging as the most prominent sensitive cancer type (4/10 top sensitive cell lines were NSCLC). Using the pattern matching tool from the NCI CellMiner™ platform LP-184 stands out as a unique molecule and is strongly anti-correlated in drug activity with approved DNA alkylating agents such as oxaliplatin, ifosfamide and carmustine. LP-184 activity is dependent upon the expression of Prostaglandin Reductase 1 (PTGR1). PTGR1 is upregulated in tumors with deregulated NRF2, including tumors with mutations in KEAP1. We hypothesized LP-184 to be efficacious in lung cancers with KEAP1 mutations. LP-184 activity was assessed in an expanded panel of 20 NSCLC cell lines. Overall, LP-184 exhibited high activity in 16/20 NSCLC cell lines (mean IC50 570 nM, median IC50 371 nM). LP-184 IC50 values are 10-3800 fold lower than those seen for cisplatin, paclitaxel and pemetrexed. When activity of LP-184 in the cell lines was correlated with presence or absence of KEAP1 and/ or KRAS mutations, 5/7 cell lines with KEAP1 mutations and 4/5 cell lines with KRAS mutations, as well as 4/5 cell lines with dual KEAP and KRAS mutations were sensitive to LP-184. Machine learning (ML) methods were further used to develop an LP-184-specific gene signature predictive of response. Using this 40 gene signature, LP-184 showed predicted nanomolar potency in 85 of 129 NSCLC cell lines (65%) in the Cancer Cell Line Encyclopedia (CCLE) with mean IC50 100 nM and median IC50 87 nM. Of these 85, 24 cell lines have KEAP1 mutations and 25 cell lines have KRAS mutations, with 10 overlapping cell lines having both KEAP1 and KRAS mutations. In conclusion, LP-184 stands out as a unique anticancer agent that demonstrates nanomolar potency against NSCLC cell lines. ML-based gene signature of response allows biomarker-guided selection of lung cancers that might benefit the most with this agent. LP-184 could thus provide focused clinical value in the treatment of lung cancer. Citation Format: Aditya Kulkarni, Jean Philippe Richard, Umesh Kathad, Michael Seddon, Terri Lehman, Rama Modali, Panna Sharma. LP-184, a molecule with nanomolar potency, exhibits strong activity in lung cancers with KEAP1 and KRAS mutations [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 4185.