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Concurrent HER or PI3K Inhibition Potentiates the Antitumor Effect of the ERK Inhibitor Ulixertinib in Preclinical

Hongmei Jiang¹, Mai Xu¹, Lin Li¹

¹Division of Oncology, Department of Internal Medicine, Washington University School of Medicine, Saint Louis, Missouri.

Molecular Cancer Therapeutics

|August 2, 2018

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.

Insights

Ulixertinib, an ERK-specific inhibitor, shows promise for pancreatic cancer treatment. Combining it with other targeted therapies may overcome resistance and improve outcomes in pancreatic ductal adenocarcinoma (PDAC).

Area of Science:

Oncology
Molecular Biology
Cancer Therapeutics

Background:

Pancreatic ductal adenocarcinoma (PDAC) lacks effective treatments, with KRAS mutations being a major challenge.
Targeting the RAF-MEK-ERK pathway is a strategy, but RAF/MEK inhibitors show limited efficacy in PDAC due to resistance mechanisms.
ERK-specific inhibitors offer a promising approach to effectively block this critical oncogenic pathway.

Purpose of the Study:

To evaluate the efficacy of ulixertinib, an ERK-specific inhibitor, in preclinical models of PDAC.
To investigate the mechanisms of resistance to ulixertinib in PDAC and identify potential combination strategies.
To provide a preclinical rationale for clinical trials of ulixertinib in PDAC patients.

Main Methods:

Testing ulixertinib's effect on PDAC cell line growth in vitro.
Assessing the potentiation of gemcitabine's cytotoxic effects by ulixertinib.
Analyzing the activation of the PI3K-AKT pathway and HER/ErbB proteins in response to ulixertinib.
Evaluating combination therapies of ulixertinib with PI3K or HER inhibitors in vitro and in vivo.

Main Results:

Ulixertinib demonstrated significant inhibition of PDAC cell growth in vitro.
Ulixertinib enhanced the cytotoxic effects of gemcitabine.
PDAC cells treated with ulixertinib upregulated the PI3K-AKT pathway via HER/ErbB activation.
Combined inhibition of PI3K or HER synergized with ulixertinib to suppress PDAC growth.

Conclusions:

Ulixertinib shows preclinical efficacy against PDAC and can overcome resistance mechanisms.
Combination therapy with ulixertinib and PI3K or HER inhibitors offers a promising strategy for PDAC treatment.
These findings support the clinical investigation of ulixertinib-based combinations in PDAC patients.

Read full analysis

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