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Ulixertinib (BVD-523) is a first-in-class and best-in-class small molecule inhibitor of ERK1/2 currently being investigated in several oncology clinical trials, both as a single agent and in combination with other therapeutics. Ulixertinib has demonstrated efficacy in patients with tumors harboring alterations within the RAS-MAPK pathway. KRAS is the most frequently mutated oncogene in cancer and is a key mediator of the RAS-MAPK signaling pathway resulting in proliferation and cellular growth. The specific KRASG12C mutation occurs in approximately 10% of non-small cell lung cancer (NSCLC), 3% of colorectal cancer, and 1-2% across all other tumor types. KRASG12C mutant-inhibitors, including AMG-510 (sotorasib), MRTX849 (adagrasib), and JDQ443 have demonstrated efficacy in KRASG12C-mutant cancers, including NSCLC. Clinically described mechanisms of acquired resistance to KRASG12C inhibitors converge on reactivation of the RAS-MAPK pathway. We hypothesized combining ulixertinib with a KRASG12C inhibitor would circumvent resistance to single agent KRASG12C inhibition, generating increased magnitude and duration of response compared to either single agent alone. The efficacy of ERK1/2 inhibitor, ulixertinib, in combination with KRASG12C inhibitor, adagrasib, was assessed in cell line derived xenograft models harboring KRASG12C mutations. Models were selected based on response to single agent adagrasib, ranging from sensitive to partially responsive. Combination treatment resulted in superior tumor growth inhibition compared to dosing of either single agent. RNA sequencing was performed on tumor samples that were collected 2 hours after the last dose of treatment. Expression of the mutant KRAS alleles were readily confirmed from RNA sequencing data in all models. Gene expression analysis showed differential expression of MAPK pathway genes in monotherapy versus combination therapy treated groups. In summary, ulixertinib combined with adagrasib exhibited robust pre-clinical activity in a variety of xenograft models with KRASG12C and should be further evaluated. Citation Format: Deborah Knoerzer, Anupama Reddy, Jessica A. Box, Anna Groover, Brent Kreider, Martin Teresk, Caroline M. Emery. The combination of ulixertinib (ERK1/2 Inhibitor) and KRASG12C inhibition demonstrates significant efficacy in preclinical models [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 2692. |
