Abstract 5499: Synergistic effects of the combination of ERK1/2 with EGFR, KRASG12C, CDK4/6, and PD-L1 inhibition for cancer treatment

Abstract

Abstract Background: Mitogen-activated protein kinase (MAPK) cascade is a key pathway that regulates a wide variety of cellular processes, which is frequently activated in cancers. Many nods of the MAPK pathway are considered as promising anti-tumor drug targets, such as RTKs, KRASG12C, RAF, MEK1/2, and ERK1/2. Multiple inhibitors targeting proteins on MAPK pathway have been developed for cancer treatment. However, the effectiveness of these inhibitors is often limited due to acquired drug resistance via pathway feedback activation, indicating the necessity of combination strategies to help block reactivation or bypass activation of MAPK pathway. ATG-017 is an oral, potent, and highly selective inhibitor of ERK1/2, which is under Phase 1 clinical investigation. This study tested the in vivo antitumor effects induced by the combination of ATG-017, with EGFR inhibitor (Osimertinib), KRASG12C inhibitor (ATG-012), CDK4/6 inhibitor (Abemaciclib) or PD-L1 inhibitor (Atezolizumab), in preclinical tumor models. Methods: The in vivo combinations of the drugs were tested in NCI-H1975, NCI-H358 (non-small cell lung cancer) or EL4 (T cell Lymphoma) CDX mouse models. The tumor bearing mouse were treated with vehicle control, ATG-017 (15 or 25 mg/kg, QD), Osimertinib (1mg/kg, QD), ATG-012 (10mg/kg, QD), Abemaciclib (25mg/kg, QD), Atezolizumab (10mg/kg, BIW) or the combination for 9 to 21 days. The tumor size was measured twice a week and tumor growth inhibition (TGI) was evaluated compared with vehicle group. Tumor tissues were collected for tumor infiltrating lymphocyte (TIL) analysis using Flow cytometry or multiplex IHC. Results: In the NCI-H1975 CDX in vivo study, the monotherapy of ATG-017 and Osimertinib induced TGIs of 61.95% and 79.18%, respectively on day 17 after grouping. The combination of ATG-017 and Osimertinib showed 101.85% TGI. In the NCI-H358 CDX in vivo study, the monotherapy of ATG-017, ATG-012, and combination induced TGI of 44.29%,73.71% and 97.13%, respectively on day 8 after grouping. The monotherapy of ATG-017, Abemaciclib, and the combination induced TGIs of 91.40%,63.10% and 108.15%, respectively on day 20 after grouping. In the EL4 syngeneic T cell lymphoma model, neither ATG-017 nor Atezolizumab showed single agent activity, while the combination induced a significant TGI of 21.86% on day 9 after grouping. The percentage of infiltrating CD8+ T cells, CD8:CD4 ratio and M1:M2 macrophage ratio were found increased in the combination group, suggesting the potential role of ATG-017 plus PD-L1 inhibitor in changing a “cold” tumor towards a “hot” phenotype. Conclusion: Strong synergism has been observed for the combination of ATG-017 with EGFR, KRASG12C, CDK4/6, and PD-L1 inhibition, suggesting promising therapeutic strategies for cancer patients that warrants further investigation. Citation Format: Ya Kong, Peng Chen, Lulu Jiang, Bin Jiang, Jay Mei, Bo Shan, Bing Hou. Synergistic effects of the combination of ERK1/2 with EGFR, KRASG12C, CDK4/6, and PD-L1 inhibition for cancer treatment. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5499.