Abstract LB-271: Insight towards therapeutic susceptibility of KRAS mutant cancers from MRTX1257, a novel KRAS G12C mutant selective small molecule inhibitor
Authors: Christensen James G. , Fell Jay B. , Marx Matthew A. , Fischer John , Hallin Jill , Calinisan Andrew , Baer Brian , Burkhard Michael , Blake James , Vigers Guy , Aranda Ruth , Hargis Lauren , Briere David , Engstrom Lars , Olson Peter 
Published: August 2019

The ability to effectively target mutated KRAS has remained elusive despite decades of research. By solving a series of co-crystal structures coupled with iterative structure-based drug design, substituted tetrahydropyridopyrimidines were identified as selective, covalent inhibitors of mutant KRAS G12C. MRTX1257 emerged as a research tool compound that demonstrates the ability to irreversibly modify KRAS G12C, trap it in its inactive GDP-bound state, and inhibit ERK1/2 with an IC50 value of 1 nM. Therefore, studies were designed to provide insight towards the breadth of therapeutic response and the underlying molecular mechanisms of MRTX1257 activity. The evaluation of an extended panel of KRAS G12C mutant cell lines in cell viability assays indicated broad anti-tumor activity with a variable concentration-response pattern (0.2-62 nM). MRTX1257 also demonstrated 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 level which demonstrated near-complete KRAS target inhibition with broad spectrum anti-tumor activity including deep tumor regressions in approximately 80% of all models evaluated across a large panel of KRAS G12C-mutant cell-derived and patient-derived xenografts (n = 23). MRTX1257 was inactive in non-KRAS G12C-mutant cell lines in vitro and in vivo. The antitumor response across tumor models varied in KRAS G12C positive models from durable complete tumor regression to tumor stasis. 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, signal transduction and feedback signaling pathways were evaluated. In a temporal pattern consistent with drug tolerance kinetics, MAP kinase pathway reactivation was observed following continuous treatment based on rebound of pERK and pS6 signaling. Also consistent with signaling rebound dynamics and drug tolerance, down-regulation of dual specificity phosphatases (DUSPs), Sprouty family (SPRY), and ETVs along with decoupling of cell cycle from KRAS regulatory constraints was observed. CRISPR and small molecule combination screens identified mTOR, SHP2, EGFR family, and cell cycle kinases as targetable vulnerabilities in partially tolerant KRAS G12C mutant models. Based on these observations, a number of combination strategies designed to co-target signaling feedback pathways were evaluated in tumor models and provided insight into the importance of rebound pathways. Together, these data indicate the therapeutic susceptibility and broad dependence of KRAS G12C mutation-positive tumors and provide insight toward the molecular basis of response to single agent and combinatorial therapies.

Citation Format: James G. Christensen, Jay B. Fell, Matthew A. Marx, John Fischer, Jill Hallin, Andrew Calinisan, Brian Baer, Michael Burkhard, James Blake, Guy Vigers, Ruth Aranda, Lauren Hargis, David Briere, Lars Engstrom, Peter Olson. Insight towards therapeutic susceptibility of KRAS mutant cancers from MRTX1257, a novel KRAS G12C mutant selective small molecule inhibitor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-271.