Concurrent HER or PI3K inhibition potentiates the antitumor effect of the ERK inhibitor ulixertinib in preclinical pancreatic cancer models

Hongmei Jiang, Mai Xu, Lin Li, Patrick Grierson, Paarth Dodhiawala, Maureen Highkin, Daoxiang Zhang, Qiong Li, Andrea Wang-Gillam, Kian Huat Lim

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

Effective treatment for pancreatic ductal adenocarcinoma (PDAC) is an urgent, unmet medical need. Targeting KRAS, the oncogene that is present in >95% of PDAC, is a heavily pursued strategy, but remains unsuccessful in the clinic. Therefore, targeting key effector cascades of KRAS oncopro-tein, particularly the mitogenic RAF-MEK-ERK pathway, represents the next best strategy. However, RAF or MEK inhibitors have failed to show clinical efficacy in PDAC. Several studies have shown that cancer cells treated with RAF or MEK inhibitors adopt multiple mechanisms to reactivate ERK signaling. Therefore, development of ERK-specific inhibitors carries the promise to effectively abrogate this pathway. Ulixertinib (or BVD-523) is a first-in-class ERK-specific inhibitor that has demonstrated promising antitumor activity in a phase I clinical trial for advanced solid tumors with NRAS and BRAF mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits in vitro growth of multiple PDAC lines and potentiates the cytotoxic effect of gemcitabine. Moreover, we found that PDAC cells treated with ulixertinib upregulates the parallel PI3K-AKT pathway through activating the HER/ErbB family proteins. Concurrent inhibition of PI3K or HER proteins synergizes with ulixertinib in suppressing PDAC cell growth in vitro and in vivo. Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients.

Original languageEnglish
Pages (from-to)2144-2155
Number of pages12
JournalMolecular Cancer Therapeutics
Volume17
Issue number10
DOIs
StatePublished - Oct 2018

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