Abstract 7274: Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model
Authors: Navarro Valeria Estrada , Panneton Vincent , Dong Lauren , Choi Hyejin , Venkatesh Divya , Maniyar Rachana , Schulze Isabell , Wolchok Jedd D. , Merghoub Taha 
Published: March 2024

Abstract
Cysteine-binding targeted drugs AMG-510 and MRTX-849 provide a new therapeutic approach for advanced KRASG12C mutant cancers. However, clinical response has been limited. Responders eventually develop adaptive resistance by gaining additional MAPK pathway mutations, resulting in limited therapeutic benefit. High-dose pulsatile treatment with MAPK pathway inhibitors has been proposed as an alternative strategy to alleviate adaptive resistance while maintaining tumor control. The sensitivity of tumor cells to pan-inhibitors of the MAPK pathway, crucial for proliferation, creates a therapeutic opportunity window for immune cells to restore their function during an intermittent regimen. Congruently, we have previously shown that intermittent pan-MAPK pathway inhibitor treatment delays drug resistance, supports T cell activation, and enhances tumor delay when combined with immunotherapy. In this study, we investigated the effects of continuous and pulsatile KRASG12C inhibition on tumor and immune cells in order to design combinatorial strategies with immune-modulating agents that overcome drug resistance. Our data suggest that a weekly single high-dose regimen of AMG-510 is less effective at achieving tumor control in preclinical mouse models of KRAS mutant lung cancer compared to daily treatments. However, supplementing this pulsatile regimen with lower maintenance doses markedly slows the growth of LLC KRASG12C lung cancer. Flow cytometry analysis revealed that high-dose pulse regimen enhances T cell activation, evidenced by increased expression of TCF-1, Ki67, PD-1, and GITR, along with lower expression of co-inhibitory molecules Lag-3 and Tim-3, 3 days after treatment. In vitro, AMG-510 also improves the antigen presentation of OVA-expressing LLC-KML lung cancer cells via MHC class I and, to a lesser extent, MHC class II. Furthermore, we found that while combinatorial therapy with PD-1 blockade alone does not significantly impact tumor control, the combination with CTLA-4 blockade shows efficacy across pulsatile and continuous AMG-510 dosing cohorts. Overall, our findings suggest that the utilization of intermittent dosing regimens for selective KRASG12C inhibitors is a promising approach for improving clinical responses in lung cancers with KRAS mutations. Future experiments will aim to delineate MAPK pathway behavior in vivo and in vitro under pulsatile and continuous treatment, assess immunogenicity, and further characterize immune changes in the different treatment regimens, with the goal of designing more efficient cancer therapies utilizing selective KRAS inhibitors.
Citation Format: Valeria Estrada Navarro, Vincent Panneton, Lauren Dong, Hyejin Choi, Divya Venkatesh, Rachana Maniyar, Isabell Schulze, Jedd D. Wolchok, Taha Merghoub. Optimization of intermittent dosing strategies of KRAS G12C inhibitors in preclinical lung cancer model [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 7274.