Abstract IA19: Insight towards therapeutic susceptibility of KRAS-mutant cancers from MRTX1257, a novel KRAS G12C mutant-selective small-molecule inhibitor
Authors: Christensen James G. 
Published: June 2021

The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a highly informative set of ligand-complexed co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors of mutant KRAS G12C. MRTX1257 emerged from this chemical series as a research tool compound that demonstrates the ability to irreversibly bind to the KRAS G12C variant, trap it in the inactive GDP-bound state, and inhibit ERK1/2 phosphorylation with an IC50 value of 1 nM. Therefore, a number of studies with MRTX1257 (and other prototype inhibitors) were designed to provide insight towards the breadth of therapeutic response and the underlying molecular mechanisms of sensitivity and resistance to KRAS inhibition. The evaluation of an extended panel of KRAS G12C mutant cell lines in cell viability and survival assays indicated that the vast majority of cell lines responded at concentrations under 50 nM, but that the concentration-response range varied by two orders of magnitude (0.2-62 nM). To extend these analyses to in vivo studies, MRTX1257 demonstrated clear evidence of dose-dependent irreversible modification of KRAS G12C and inhibition of KRAS-dependent signal transduction in multiple KRAS G12C mutant tumor models. MRTX1257 was then evaluated at a fixed dose that yielded near-complete KRAS target inhibition across an additional large panel of KRAS G12C-mutant subcutaneous cell-derived and patient-derived xenografts and demonstrated broad-spectrum antitumor activity including frank tumor regressions (often exceeding 50% tumor reduction) in approximately 80% of all models evaluated (n = 23). In contrast, MRTX1257 was inactive in non-KRAS G12C-mutant cell lines in vitro and tumor models in vivo, indicating that the antitumor activity of this molecule was mediated through binding to and inhibition of the KRAS G12C variant. The antitumor response across tumor models varied in KRAS G12C positive models from complete tumor regression with no evidence of recovery after treatment cessation, to partial response, to tumor stasis. In addition, a small subset of models demonstrated rapid initial tumor regression followed by tumor stasis, suggesting that there may be mechanisms of adaptive tolerance to MRTX1257 treatment. Based on this response pattern, temporal effects on signal transduction and molecules implicated in feedback signaling were evaluated. In a temporal pattern consistent with drug tolerance kinetics, MAP kinase pathway reactivation was observed based on rebound of pERK and pS6 signaling despite continuous treatment. Also consistent with signaling rebound dynamics and drug tolerance, downregulation of dual specificity phosphatases (DUSPs), Sprouty family (SPRY), and ETVs along with decoupling of cell cycle from KRAS regulatory constraints was observed. Based on these observations, a number of combination strategies designed to co-target signaling feedback pathways were evaluated in tumor models and provided direct insight into the importance of rebound pathways and response and the practical value of rational combination approaches. Together, these data indicate the therapeutic susceptibility and broad dependence of KRAS G12C mutation-positive tumors on KRAS for tumor cell growth and survival and provide insight toward the molecular basis of response to single-agent and combinatorial therapies.

Citation Format: James G. Christensen. Insight towards therapeutic susceptibility of KRAS-mutant cancers from MRTX1257, a novel KRAS G12C mutant-selective small-molecule inhibitor [abstract]. In: Proceedings of the AACR Special Conference on Targeting RAS-Driven Cancers; 2018 Dec 9-12; San Diego, CA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(5_Suppl):Abstract nr IA19.