ERK Mutations and Amplification Confer Resistance to ERK-Inhibitor Therapy

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
Bijay S JaiswalSomasekar Seshagiri

Abstract

Purpose: MAPK pathway inhibitors targeting BRAF and MEK have shown clinical efficacy in patients with RAF- and/or RAS-mutated tumors. However, acquired resistance to these agents has been an impediment to improved long-term survival in the clinic. In such cases, targeting ERK downstream of BRAF/MEK has been proposed as a potential strategy for overcoming acquired resistance. Preclinical studies suggest that ERK inhibitors are effective at inhibiting BRAF/RAS-mutated tumor growth and overcome BRAF or/and MEK inhibitor resistance. However, as observed with other MAPK pathway inhibitors, treatment with ERK inhibitors is likely to cause resistance in the clinic. Here, we aimed to model the mechanism of resistance to ERK inhibitors.Experimental Design: We tested five structurally different ATP-competitive ERK inhibitors representing three different scaffolds on BRAF/RAS-mutant cancer cell lines of different tissue types to generate resistant lines. We have used in vitro modeling, structural biology, and genomic analysis to understand the development of resistance to ERK inhibitors and the mechanisms leading to it.Results: We have identified mutations in ERK1/2, amplification and overexpression of ERK2, and overexpression of EGFR/ERB...Continue Reading

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Citations

Sep 5, 2019·Cells·João M A DelouHelena L Borges
Jun 16, 2019·International Journal of Molecular Sciences·Monserrat Olea-FloresNapoleón Navarro-Tito
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Dec 1, 2020·Pharmacology & Therapeutics·Bingjian WenZhengquan Su
May 17, 2021·Seminars in Cancer Biology·Rahim UllahLixin Wan

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