Abstract LB264: Oncogenic KRASG12C dependency in colorectal cancer

Abstract

Background: Oncogenic KRAS mutations occur in 50% of colorectal cancer (CRC) patients and have long been considered undruggable. Novel covalent inhibitors targeting the KRASG12C mutation have been developed, presenting a unique opportunity to directly target KRAS. However, clinical trials focusing on sotorasib reveal that KRASG12C inhibitors are only modestly active in CRC compared to lung cancer patients with response rates being 7% and 54%, respectively. Adaptive and acquired feedback has contributed to the diminished therapeutic efficacies observed in CRC patients. Recent studies have shown that receptor tyrosine kinases may be the conduit for adaptive feedback to KRASG12C inhibition, with EGFR being the focus of this class. However, while preclinical and clinical studies evaluating combinatorial strategies to maintain the inactivation of KRASG12C have proven that adaptive feedback can be overcome through combinations, the acquired resistance mechanisms remain unclear. In this study, we examine the adaptive and acquired response to KRASG12C inhibition using PDX-CRC models. Methods: We treated three KRASG12C PDX-CRC cell lines (B8182, C1047, and F3008) with sotorasib, panitumumab, and the combo of the two drugs for 6h and 24h. We compare their response to untreated samples to understand the adaptive response over time. Adaptive response to treatment was assessed by measuring the pERK and pEGFR response via western blots. We also treated two KRASG12C PDX-CRC mouse models, B8026 and C1177, with sotorasib, panitumumab, trametinib, as well as doublet and triplet combos with sotorasib. We then assessed treatment response by measuring tumor volume. To develop PDX-CRC models that acquire resistance to sotorasib, we treated the mice continuously with sotorasib over time until we observed noticeable tumor growth. Results: B8182, C1047, and F3008 all show adaptive response to sotorasib. However, while the source of adaptive response is not clear, our data suggests that EGFR may not be the driver in all three cell lines. In our PDX-CRC mouse models, both B8026 and C1177 are responsive to sotorasib and panitumumab. However, C1177 was not responsive to trametinib. Both models however are responsive to doublet combos of sotorasib with either agent, with triplet combo providing the greatest effectiveness in reducing tumor volume. Additionally, B8026 and C1177 PDX-CRC models developed acquired resistance to sotorasib. Conclusion: KRASG12C inhibitors are only modestly active in CRC. Treatment of sotorasib in KRASG12C PDX-CRC cell lines showed that EGFR may not be the primary mediator of adaptive resistance in all models. However, inactivation of KRASG12C can be maintained through combinations targeting the kinases involved in the feedback mechanisms. Finally, while functional characterization of resistance mechanisms is underway, the mechanisms of resistance to KRASG12C appear to be transcriptomic. Citation Format: Oluwadara Coker, Alexey Sorokin, Kelly Gale, Fengqin Gao, John Paul Shen, Lawrence Kwong, Ji Wu, Hey Min Lee, Melanie Woods, Oscar Villareal, Scott Kopetz. Oncogenic KRASG12C dependency in colorectal cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr LB264.