Targeting KRAS proteoastasis to develop personalized therapies for lung cancer patients

A high heterogeneity within KRAS mutant lung tumors challenges the attempts to rationally design drug combinations for this group of patients.  The loss of heterozygosity of LZTR1, a gene coding a proteostatic regulator of KRAS, significantly co-occurs with KRAS mutations in lung adenocarcinoma.  We hypothesize that dysregulation of KRAS proteostasis might contribute to the heterogeneity of KRAS signaling and promotes lung cancer progression, affecting the drug response and leading to therapy resistance.  This project aims to unvocer the molecular mechanism leading to LZTR1-driven tumor heterogeneity and identify therapeutic vulnerabilities of LZTR1-deleted lung cancer.  Specifically, our goal is to interrogate changes in the tumor microenvironment and intracellular signaling mediated by the proteostatic dysregulation of KRAS.  We believe that understanding the complexities of RAS biology may be translated into novel therapies for patients with KRAS-mutated cancers.