Target discovery and combination therapy in KRAS mutant cancer

Division Of Basic Sciences - Nci

Investigators

Linked publications, trials & patents

Abstract

BACKGROUND. The KRAS oncogene is a primary driver in lung, pancreatic, and colorectal cancers. However, patients often rapidly develop resistance to KRAS inhibitors, highlighting the need for drug combinations that can prevent or delay this resistance and extend treatment effectiveness. While kinase inhibitors targeting Ras effector pathways (MAPK and PI3K) have been developed, they have not shown clinical efficacy against KRAS mutant tumors. Historically, targeted therapies have focused on blocking oncogenic addiction (OA), with less attention given to blocking non-oncogenic addiction (NOA) in KRAS mutant cells. Co-targeting both NOA and OA could lead to more effective drug combinations with a better therapeutic window and more durable responses in KRAS mutant tumors. OBJECTIVES. 1) to use functional genomic screens to identify functional dependencies resulting from oncogene (OA) and non-oncogene addiction (NOA) in KRAS mutant cancer cells; 2) to evaluate mechanism of selectivity of targeted therapies in KRAS mutant cells, 3) to investigate mechanism leading to drug resistance; and 4) To identify orthogonal drug combinations that target distinct aspects of OA and NOA in KRAS mutant cells. MAJOR ACTIVITIES, SIGNIFICANT RESULTS AND KEY OUTCOMES. 1) Discovery of NOA targets in KRAS mutant cells. Our research aims to identify critical functional vulnerabilities in KRAS-mutant cancer cells through genetic screens. By performing loss-of-function screens with pooled CRISPR/Cas9 gene knockout libraries, we have discovered druggable genes vital for the anchorage-independent growth of these cells. We are currently delving into the molecular mechanisms of these genes and seeking small molecule inhibitors to develop new targeted therapies. 2) Mechanisms of resistant to Ras pathway inhibitors. Resistance to Ras pathway inhibitors is a significant challenge in cancer treatment. To address this, we have analyzed the mechanisms driving resistance to both KRAS and MEK inhibitors across various KRAS-mutant cancer cell lines (colorectal, pancreatic, lung, and multiple myeloma). We are currently working to understand the molecular mechanism leading to drug resistance and uncover ways to reverse these resistance mechanisms, which could lead to improved therapeutic responses in preclinical models. 3) Identification of novel drug combinations for KRAS mutant cancer. To develop more effective treatments for KRAS-mutant cancers, we are evaluating drug combinations through both high-throughput screening and a hypothesis-driven approach. Our strategy involves combining inhibitors that block oncogenic Ras signaling (targeting Ras oncogenic addiction, or OA) with inhibitors that amplify oncogenic stress (targeting non-oncogenic addiction, or NOA pathways). We assess the therapeutic window by comparing the drug combinations' toxicity in KRAS-mutant cancer cells against normal epithelial cells. Promising combinations are then tested for their efficacy against KRAS-driven tumors in vivo using mouse xenograft and autochthonous models.