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 , 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 and mutations, providing a strong rationale to test this inhibitor in PDAC. In this study, we show that ulixertinib effectively inhibits 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 and Overall, our study provides the preclinical rationale for testing combinations of ulixertinib with chemotherapy or PI3K and HER inhibitors in PDAC patients..

NRG1 Gene Fusions Are Recurrent, Clinically Actionable Gene Rearrangements in KRAS Wild-Type Pancreatic Ductal Adenocarcinoma

“…It is therefore perhaps likely that resistance mechanisms in HER-family-driven PDAC will emerge from the acquisition of genomic alterations that activate parallel signaling pathways. With respect to possible therapeutic strategies, a recent study has demonstrated that concurrent inhibition or HER-family kinases synergizes with an ERK-specific inhibitor in suppressing PDAC cell growth in vitro and in vivo (35). This provides a rationale for testing combinations of targeted therapies in preclinical models, as has been demonstrated for cancers treated with BRAF inhibitors (36,37).…”

“…Upregulation of NRG1 is a well-documented mechanism of parallel pathway activation and resistance in HER2-positive breast cancer models (31,32) and ALK-positive lung cancer (33,34). Furthermore, it has been reported that PDAC cells treated with an ERK-specific inhibitor upregulated the parallel PI3K-AKT pathway through activating HER-family proteins (35). It is therefore perhaps likely that resistance mechanisms in HER-family-driven PDAC will emerge from the acquisition of genomic alterations that activate parallel signaling pathways.…”

Molecular alterations and targeted therapy in pancreatic ductal adenocarcinoma

“…Everolimus, an mTOR inhibitor [ 73 ], failed equally against metastatic PDAC (the median progression-free survival (PFS) was 1.8 months and the median OS was 4.5 months) [ 74 ]. Recent studies also aimed to combine PI3K inhibitors with other targeted treatments, such as MK-2206 plus selumetinib (the OS was shorter in the experimental arm, HR = 1.37, P value = 0.15) [ 75 ], and GDC-0941 plus ulixertinib (synergistic inhibitory activity in PDAC cell lines) [ 76 ].…”

Mission Possible: Advances in MYC Therapeutic Targeting in Cancer

“…Kinase inhibitors that affect the active pS62-MYC state include ERK, CDK2, and CDK9 inhibitors [103][104][105][106][107][108][109]. Unfortunately, cancer cells are quite adept at rewiring signaling pathways in response to targeted therapies in order to keep MYC and other signaling substrates active [110][111][112].…”