Target discovery and combination therapy in KRAS mutant cancer

Division Of Basic Sciences - Nci

Investigators

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Abstract

BACKGROUND. The KRAS oncogene is a driver mutation in a significant fraction of lung, pancreatic and colorectal cancers. Recently breakthroughs with inhibitors targeting the KRAS-G12C mutant is the first Ras targeted therapies in decades. For other KRAS mutant tumors, there are no effective targeted therapies. Resistance to KRAS inhibitors develop rapidly in cancer patients, and drug combination that can prevent or delay drug resistant are needed to extend the durability of response in patients. In addition to Ras, kinases inhibitors against Ras effector pathways have been developed to target the MAPK and PI3K pathways. However, these agents have not demonstrated efficacy in clinical trials against KRAS mutant tumors. Thus far, targeted therapies have primarily focused on blocking OA, and less attention have been devoted to blocking NOA in KRAS mutant cells. Co-targeting NOA and OA together could lead to better drug combinations with orthogonal therapeutic modalities, improved therapeutic window, and more durable response in KRAS mutant tumors. OBJECTIVES. 1) Using functional genomic screens to identify genetic dependencies resulting from oncogene addiction (OA) and non-oncogene addiction (NOA) in KRAS mutant cancer cells; 2) Evaluating the mechanism, selectivity of targeted therapies in KRAS mutant cells, and the mechanisms leading to drug resistance; and 3) Identify drug combinations that orthogonally target distinct aspects of OA and NOA in KRAS mutant cells to achieve better therapeutic window. MAJOR ACTIVITIES, SIGNIFICANT RESULTS AND KEY OUTCOMES. 1) Genetic screens to identify functional vulnerabilities in KRAS mutant cancer cells. Using pooled CRISPR/Cas9 gene KO libraries, we have carried out loss-of-function screens in KRAS mutant cancer cells under different culture conditions. We have identified a candidate, druggable gene that is critical for the anchorage-independent growth of KRAS mutant cells, and we are currently investigating the mechanism of this genetic dependency and exploring small molecule inhibitors of this target. 2) Mechanisms of drug resistant to Ras pathway inhibitors. Using different KRAS mutant cancer cell lines including colorectal, pancreatic, lung, and multiple myeloma cells, we have evaluated genetic and post-transcriptional mechanisms that contribute to resistance to KRAS inhibitors and MEK inhibitors. We are currently elucidating how these resistance mechanisms can be reversed to improve therapeutic response in pre-clinical models. 3) Identification of novel drug combinations for KRAS mutant cancer. Using high-throughput drug screen and hypothesis-driven approach, we are evaluating drug combinations that involve inhibitors targeting Ras OA to block oncogenic Ras signaling and inhibitors targeting NOA pathways to exacerbate oncogenic stress in KRAS mutant cancer cells. We contrast the toxicity of drug combinations in KRAS mutant cancer cells against that in normal epithelial cells to assess the therapeutic window, and we use mouse xenograft and autochthonous tumor models to evaluate the drug combination's efficacy against KRAS-driven tumors in vivo.