Abstract 1926: MRAS the forgotten member of the GTPase superfamily plays a role in KRASG12Ci resistance

Abstract KRASG12C inhibitors have achieved impressive results in the clinic. However, intrinsic or acquired resistance to therapy invariably develops leading to disease progression in most treated patients. Emerging pre-clinical and clinical evidence points to multiple mechanisms being responsible for resistance to KRASG12C inhibitors, including receptor tyrosine kinase (RTK) activation, KRASG12C amplification, activation of alternative signaling pathways including PI3K, mTOR, YAP/TAZ, acquisition of KRAS mutations that would preclude compound binding (e.g. R68S, Y96C/D, H95D/Q/R), conversion of the G12C codon mutation, and additional activating KRAS mutations (G13D, Q61H). In the clinic, many of the described mutations were detected at low frequency, some patients displayed multiple mutations and in 40% of patients no potential driving mutations were identified. It is therefore likely that other non-genetic alterations are also involved in resistance to KRASG12Ci monotherapy. Here, we used preclinical models of KRASG12C non-small cell lung cancer (NSCLC) and colorectal cancer (CRC) to study intrinsic and acquired resistance to KRASG12C inhibitors. Increased expression of the RAS superfamily gene MRAS was observed in most KRASG12C-naïve tumor cells upon treatment with a KRASG12C inhibitors. In line with this, we observed an increase of MRAS-GTP levels in cells treated with KRASG12Ci in vitro. Interestingly, the increase in active MRAS did not lead to concomitant upregulation of MAPK signaling. Long term treatment with adagrasib was used for generating in vitro and in vivo KRASG12C models with acquired resistance to KRASG12Ci. A strong increase in MRAS expression was observed under these conditions, that surpassed the levels seen with short term treatment in naïve models. This data suggests that activation of MRAS-SHOC2-PP1C complex may play a role in compensating for the KRASG12C-driven signaling in both the intrinsic and acquired resistance setting. Knockdown of SHOC2 to baseline levels resulted in re-sensitization to KRASG12Ci monotherapy and to the effects of combinations in adagrasib-resistant NCI-H358 NSCLC cells. Pathway suppression was deepened by combining adagrasib with either a SOS1i (e.g. BI-3406) or SHP2i (e.g. TNO155) resulting in enhanced anti-tumor effects observed in the KRASG12Ci-resistant models. Our findings underscore the role of MRAS in acquired resistance in KRASG12Ci and the potential to overcome this with vertical pathway combinations, such as SOS1i or SHP2i. Citation Format: Venu Thatikonda, Kaja Kostyrko, Sabine Jurado, Simone Lieb, Melanie Hinkel, Donat Alpar, Oliver Bergner, Astrid Jeschko, Mark Pearson, Marco H. Hofmann. MRAS the forgotten member of the GTPase superfamily plays a role in KRASG12Ci resistance [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1926.