Abstract A014: Identifying and overcoming resistance to RAS targeted therapy in colorectal cancer

Abstract

Abstract KRAS is the most frequently mutated oncogene in human cancer and a potent oncogenic driver. In colorectal cancer (CRC), pathogenic KRAS mutations are observed in up to 50% of cases, yet there is little understanding of how distinct mutations dictate tumor biology including initiation, progression and therapy response. The recent approval of targeted KRASG12C inhibitors brings promise to transform the therapeutic landscape for many patients who lack effective, personalized treatment. Clinically acquired resistance is already observed, highlighting the need to identify mechanisms of resistance and approaches to overcome them. The aim of this study is to understand how distinct Kras alterations drive tumorigenesis and identify reasons underlying the failure of KRAS inhibitors in CRC. To explore the clinical significance of distinct KRAS mutations in tumor development and therapy response, we used Cre- conditional (Lox- stop- Lox) Kras mutant mouse strains crossed to the colon specific promoter Fabp1-Cre and Apc(flox/flox) mice. In the absence of Apc, we demonstrated that distinct Kras mutations G12C and G13D drive unique phenotypes in the colon which demonstrates that subtle mutational changes can dramatically alter the physiological response in vivo, and make distinct KRAS alleles an attractive target for targeted therapeutics. In tumor bearing models of CRC, we observed that KrasG12D drives large numbers of smaller tumors, while KrasG13D drives smaller numbers of larger tumors. To investigate the differences observed in tumorigenesis, we are studying the potential role of Kras to prime the colon for APC loss and the consequences of Kras alterations on the stem cell dynamics in driving tumorigenesis. Further, we employed our unique LSL-Kras mutant mouse strains and colon derived organoids to assess the therapeutic response of G12C and pan Kras inhibitors alone or in combination with upstream target drugs including inhibitors targeting EGFR signaling (EGFR, SHP2, SOS1 and MEK) and the Wnt signaling pathway. Together, this work has identified that distinct mutations in KRAS creates colon cancer specific vulnerabilities which dictates tumor biology. The unique in vivo and ex vivo organoid models provide an ideal platform to identify the underlying cause of failure of G12C inhibitors and developing effective approaches to target RAS in CRC. Citation Format: Marie J. Parsons, Maria Zafra, Sukanya Goswami, Maria Teresa Calvo Fernandez, John E. Wilkinson, Lukas E. Dow. Identifying and overcoming resistance to RAS targeted therapy in colorectal cancer [abstract]. In: Proceedings of the AACR Special Conference on Colorectal Cancer; 2022 Oct 1-4; Portland, OR. Philadelphia (PA): AACR; Cancer Res 2022;82(23 Suppl_1):Abstract nr A014.