To date, effective treatments for inoperable pancreatic ductal adenocarcinoma (PDAC) remain elusive. Targeting KRAS, the gene that is mutated in >95% of PDAC, is a heavily pursued strategy, but unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncoprotein, particularly the mitogenic RAF-MEK-ERK represents the next best strategy. However, RAF or MEK inhibitors have not shown promising clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to re-activate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. BVD-523 (ulixertinib) is a first-in-class ERK-specific inhibitor that has demonstrated anti-tumor activity in clinical trials. In this study, we showed that BVD-523 effectively inhibits transformed growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, using reverse-phase protein array analysis, we identified potential mechanisms by which PDAC cells may adopt to tolerate ERK inhibition. On this basis, we proposed and tested two rational combinatorial approaches with BVD-523 that showed promising preclinical efficacy in vitro and in mouse xenografts. Overall, we provide the first evidence that PDAC cells may readily adapt to pharmacologic ERK inhibition, and provide combinatorial therapeutic strategies that could benefit patients.

Citation Format: Hongmei Jiang, Mai Xu, Lin Li, Maureen Highkin, Daoxiang Zhang, Qiong Li, Andrea Wang-Gillam, Kian-Huat Lim. Concurrent HER or PI3K inhibition potentiates the anti-tumor effect of ERK inhibitor BVD-523 (ulixertinib) in preclinical pancreatic cancer models [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2375.