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Ref Type Journal Article
PMID (21705440)
Authors Wang H, Daouti S, Li WH, Wen Y, Rizzo C, Higgins B, Packman K, Rosen N, Boylan JF, Heimbrook D, Niu H
Title Identification of the MEK1(F129L) activating mutation as a potential mechanism of acquired resistance to MEK inhibition in human cancers carrying the B-RafV600E mutation.
Journal Cancer research
Vol 71
Issue 16
Date 2011 Aug 15
Abstract Text Although targeting the Ras/Raf/MEK pathway remains a promising anticancer strategy, mitogen-activated protein/extracellular signal-regulated kinase (ERK) kinase (MEK) inhibitors in clinical development are likely to be limited in their ability to produce durable clinical responses due to the emergence of acquired drug resistance. To identify potential mechanisms of such resistance, we established MEK inhibitor-resistant clones of human HT-29 colon cancer cells (HT-29R cells) that harbor the B-RafV600E mutation. HT-29R cells were specifically resistant to MEK inhibition in vitro and in vivo, with drug-induced elevation of MEK/ERK and their downstream targets primarily accountable for drug resistance. We identified MEK1(F129L) mutation as a molecular mechanism responsible for MEK/ERK pathway activation. In an isogenic cell system that extended these findings into other cancer cell lines, the MEK1(F129L) mutant exhibited higher intrinsic kinase activity than wild-type MEK1 [MEK1(WT)], leading to potent activation of ERK and downstream targets. The MEK1(F129L) mutation also strengthened binding to c-Raf, suggesting an underlying mechanism of higher intrinsic kinase activity. Notably, the combined use of Raf and MEK inhibitors overcame the observed drug resistance and exhibited greater synergy in HT-29R cells than the drug-sensitive HT-29 parental cells. Overall, our findings suggested that mutations in MEK1 can lead to acquired resistance in patients treated with MEK inhibitors and that a combined inhibition of Raf and MEK may be potentially useful as a strategy to bypass or prevent drug resistance in the clinic.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
MAP2K1 F129L missense gain of function MAP2K1 F129L lies within the protein kinase domain of the Map2k1 protein ( F129L confers a gain of function to the Map2k1 protein as demonstrated by increased kinase activity compared to wild-type, activation of downstream Erk signaling, and increased binding affinity to c-Raf (PMID: 21705440) and also demonstrates resistance to some Mek and Braf inhibitors (PMID: 29753091). Y
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
MAP2K1 F129L colorectal cancer sensitive RO4927350 Preclinical - Cell line xenograft Actionable In a preclinical study, a colorectal cancer cell line harboring MAP2K1 F129L demonstrated sensitivity to treatment with RO4927350 in culture and in cell line xenograft models, demonstrating inhibition of tumor growth (PMID: 21705440). 21705440