Format

Send to

Choose Destination
Cancer Res. 2014 Dec 1;74(23):7079-89. doi: 10.1158/0008-5472.CAN-14-2073. Epub 2014 Oct 15.

ERK mutations confer resistance to mitogen-activated protein kinase pathway inhibitors.

Author information

1
Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts.
2
Broad Institute, Cambridge, Massachusetts.
3
Dana-Farber Cancer Institute, Boston, Massachusetts.
4
Dana-Farber Cancer Institute, Boston, Massachusetts. Broad Institute, Cambridge, Massachusetts. Levi_Garraway@dfci.harvard.edu.

Abstract

The use of targeted therapeutics directed against BRAF(V600)-mutant metastatic melanoma improves progression-free survival in many patients; however, acquired drug resistance remains a major medical challenge. By far, the most common clinical resistance mechanism involves reactivation of the MAPK (RAF/MEK/ERK) pathway by a variety of mechanisms. Thus, targeting ERK itself has emerged as an attractive therapeutic concept, and several ERK inhibitors have entered clinical trials. We sought to preemptively determine mutations in ERK1/2 that confer resistance to either ERK inhibitors or combined RAF/MEK inhibition in BRAF(V600)-mutant melanoma. Using a random mutagenesis screen, we identified multiple point mutations in ERK1 (MAPK3) and ERK2 (MAPK1) that could confer resistance to ERK or RAF/MEK inhibitors. ERK inhibitor-resistant alleles were sensitive to RAF/MEK inhibitors and vice versa, suggesting that the future development of alternating RAF/MEK and ERK inhibitor regimens might help circumvent resistance to these agents.

PMID:
25320010
PMCID:
PMC4300142
DOI:
10.1158/0008-5472.CAN-14-2073
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center