Adaptation and Evolution of Resistance to Pan-RAS inhibition in PDAC

About This Grant

“The Adaptation and Evolution of Resistance to Pan-RAS Inhibition in Pancreatic Ductal Adenocarcinoma” Abstract: Pancreatic ductal adenocarcinoma (PDAC) kills over 52,000 people annually in the United States. The current standard therapies are chemotherapy cocktails that provide modest survival benefits along with significant side effects. For 30 years, we have known that the vast majority of PDAC cases (~94%) are driven by activating mutations in the KRAS protooncogene, but until recently, this knowledge could not be leveraged for therapeutic benefit. The recent development of drugs that selectively inhibit specific mutant variants of KRAS (including KRASG12C and KRASG12D) have demonstrated the benefit of targeting KRAS. However, these agents only work in a subset of patients whose tumors harbor these specific alleles. Furthermore, recurrence can happen rapidly as tumors can develop alternative RAS mutations that circumvent these drugs’ function. Recently, we led a large consortium in describing the preclinical performance of RMC-7977, a novel pan- RAS inhibitor that effectively inhibits the active (GTP-bound) forms of mutant and wild type KRAS, NRAS, and HRAS. Remarkably, we found that this agent was well tolerated in mice. Across multiple classes of preclinical models, RMC-7977 exhibited strong anticancer activity, and yielded the longest extension of overall survival in the (highly chemo-refractory) KPC mouse model that has been reported to date. When tumors eventually did recur, they frequently exhibited focal Myc copy number gains, providing a means to activate the downstream mitogenic programs of RAS. The investigational analog of this agent, RMC-6236, is now in Phase 3 trials after demonstrating tolerability and showing remarkable responses in the Phase 1 setting. Here, we propose to study the development of resistance to pan-RAS inhibition in PDAC. Building from our previous work, we will utilize samples from mouse- and human derived model systems as well as human clinical trial samples to understand the evolution of genetic resistance mechanisms in response to RAS inhibition. Studies will focus on how these alterations impact tumor biology and what new therapeutic vulnerabilities they may confer. In addition, we will study how short-term adaptation allows tumors to survive pan-RAS inhibition long enough to evolve genetic resistance. We found that within days of treatment, the heterogeneity of KPC mouse pancreatic tumors collapses, with selective depletion of the most aggressive, poorly differentiated malignant cells. Strikingly, we also show that RAS inhibition induces the formation of primary cilia in the malignant cells of PDAC, enabling activation of pro-survival pathways including autocrine Hedgehog signaling. We will test how targeting ciliogenesis and cilia signaling pathways may potentiate RAS inhibition by overcoming early adaptive responses to treatment. The proposed experiments will combine innovative experimental techniques, advanced computational approaches, high quality model systems, human tissues, and clinical trial samples to comprehensively study the development of resistance to pan-RAS inhibitors in PDAC.