Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical Pancreatic Cancer Models.

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 oncoprotein, 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. Mol Cancer Ther; 17(10); 2144-55. ©2018 AACR.

• Authors: Hongmei Jiang, Mai Xu, Lin Li, Patrick Grierson, Paarth Dodhiawala, Maureen Highkin, Daoxiang Zhang, Qiong Li, Andrea Wang-Gillam, Kian-Huat Lim
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 17 Issue 10 Pg. 2144-2155 (10 2018) ISSN: 1538-8514 [Electronic] United States
• PMID: 30065098 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2018 American Association for Cancer Research.

Chemical References

• Aminopyridines
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors
• Pyrroles
• ulixertinib
• ErbB Receptors
• Proto-Oncogene Proteins c-akt

Topics

• Aminopyridines (pharmacology)
• Animals
• Cell Line, Tumor
• Disease Models, Animal
• Dose-Response Relationship, Drug
• Drug Evaluation, Preclinical
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Humans
• Immunohistochemistry
• MAP Kinase Signaling System (drug effects)
• Pancreatic Neoplasms (drug therapy, metabolism, pathology)
• Phosphatidylinositol 3-Kinases (metabolism)
• Phosphoinositide-3 Kinase Inhibitors
• Protein Kinase Inhibitors (pharmacology)
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrroles (pharmacology)
• Xenograft Model Antitumor Assays