Defining New Treatment Approaches for KRAS-Mutant Lung Cancer.

摘要

Lung cancer is a deadly malignancy. The most commonly mutated oncogene we know is KRAS. We do not have a drug to inhibit KRAS , and medicinal chemistry approaches have exhausted leads. We need a new approach to find new ways to inhibit this oncogene. Objective : To identify cellular cofactors required for KRAS G12D -driven NSCLC. Specific Aim 1: To identify gene products specifically essential for KRAS-driven NSCLC, we will perform a shRNA screen of thousands of mouse genes, looking for essentiality in multiple independent cell lines derived from two NSCLC GEMMs: one RAF- dependent and one RAS-dependent. This Aim is underway and has verified that KRAS is indeed essential in the KRAS mutant mouse cell lines. Specific Aim 2: To validate our findings in human NSCLC we will test a panel of human NSCLC cell lines with known dependence on RAS for their dependence on the elements (hits) identified in Aim 1. Study Design : In vitro shRNA screen in Aim 1. Individual shRNA validation in human lines in Aim 2.