Targeted degradation of KRAS oncoproteins triggers antitumor immunity and abolishes lung tumor - Summary: Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer death worldwide. KRAS is the most frequently mutated oncogene in lung adenocarcinoma, the most common subtype of NSCLC. Approximately 30% of patients with lung adenocarcinoma harbor KRAS mutations, with G12C and G12V being the most frequent forms. Direct targeting KRAS was historically difficult until the recent development of KRAS G12C specific inhibitors, including AMG510 and MRTX849. These inhibitors have shown strong anti-tumor effects in KRAS G12C-mutated lung adenocarcinoma patients, exemplified by the recent FDA approval of AMG510 (Sotorasib). Despite this breakthrough in KRAS therapeutics, Sotorasib demonstrates a 32% response rate in patients with lung cancer and patients often develop rapid resistance. Furthermore, there are no specific inhibitors for KRAS G12V, the second most common KRAS mutation in NSCLC. Therefore, there is an urgent need to develop new strategies to improve the clinical response to KRAS G12C inhibitors, as well as to tackle KRAS G12V lung adenocarcinoma. PROteolysis TArgeting Chimeras (PROTACs)-mediated protein degradation has emerged as a powerful system to specifically target oncogenic drivers. Utilizing this PROTACs system, we have developed a versatile approach known as the degradation tag (dTAG) system, to rapidly deplete any tagged target protein in vitro and in vivo. Our preliminary study demonstrated that dTAG potently degrades oncogenic KRAS variants and abolishes lung tumors in vivo, and drives anti-tumor immunity through increasing CD8+ T and dendritic cell activity. My proposed project will leverage the dTAG system and novel KRAS G12C and G12V preclinical models (organoids and genetically engineered mouse models (GEMMs)) to further evaluate KRAS degradation as a new therapeutic approach. Furthermore, with the KRAS G12C inhibitors and immunotherapy clinical trials underway, evaluating the in vivo therapeutics of combining KRAS degradation with immunotherapy is of high significance. Overall, Aim 1 is to comprehensively evaluate efficacy of targeted degradation of oncogenic KRAS variants alone and in combination with immunotherapy in vivo. Aim 2 will dissect tumor microenvironment alterations upon degradation of oncogenic KRAS mutants alone and in combination with immunotherapy. Aim 3 will characterize the underlying cancer intrinsic and immunological mechanisms that contribute to antitumor immunity. Findings from my research will offer evidence for further evaluation of the protein degradation in targeting KRAS mutant cancers in clinical trials.To achieve these aims, I designed a 3- year plan that includes participation in scientific and career development meetings, workshops and coursework to further develop my cancer immunology and computational biology expertise. This career transition award will greatly facilitate my goal of leading a multidisciplinary research laboratory focused on addressing challenges in the treatment of lung cancer in the academic environment of an NCI-designated comprehensive cancer center.
