Allele-specific mechanisms of activation of mek1 mutants determine their properties Journal Article

Authors: Gao, Y.; Chang, M. T.; McKay, D.; Na, N.; Zhou, B.; Yaeger, R.; Torres, N. M.; Muniz, K.; Drosten, M.; Barbacid, M.; Caponigro, G.; Stuart, D.; Moebitz, H.; Solit, D. B.; Abdel-Wahab, O.; Taylor, B. S.; Yao, Z.; Rosen, N.
Article Title: Allele-specific mechanisms of activation of mek1 mutants determine their properties
Abstract: Mutations at multiple sites in MEK1 occur in cancer, suggesting that their mechanisms of activation might be different. We analyzed 17 tumor-associated MEK1 mutants and found that they drove ERK signaling autonomously or in a RAS/RAF-dependent manner. The latter are sensitive to feedback inhibition of RAF, which limits their functional output, and often cooccur with RAS or RAF mutations. They act as amplifi ers of RAF signaling. In contrast, another class of mutants deletes a hitherto unrecognized negative regulatory segment of MEK1, is RAF- and phosphorylation-independent, is unaffected by feedback inhibition of upstream signaling, and drives high ERK output and transformation in the absence of RAF activity. Moreover, these RAF-independent mutants are insensitive to allosteric MEK inhibitors, which preferentially bind to the inactivated form of MEK1. All the mutants are sensitive to an ATP-competitive MEK inhibitor. Thus, our study comprises a novel therapeutic strategy for tumors driven by RAF-independent MEK1 mutants. SIGnIfICAnCE: Mutants with which MEK1 mutants coexist and their sensitivity to inhibitors are determined by allele-specifi c properties. This study shows the importance of functional characterization of mutant alleles in single oncogenes and identifi es a new class of MEK1 mutants, insensitive to current MEK1 inhibitors but treatable with a new ATP-competitive inhibitor. © 2018 AACR.
Journal Title: Cancer Discovery
Volume: 8
Issue: 5
ISSN: 2159-8274
Publisher: American Association for Cancer Research  
Date Published: 2018-05-01
Start Page: 648
End Page: 661
Language: English
DOI: 10.1158/
PROVIDER: scopus
PUBMED: 29483135
Notes: Article -- Export Date: 2 July 2018 -- Source: Scopus
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MSK Authors
  1. Neal Rosen
    351 Rosen
  2. David Solit
    420 Solit
  3. Rona Denit Yaeger
    61 Yaeger
  4. Barry Stephen Taylor
    135 Taylor
  5. Zhan Yao
    21 Yao
  6. Matthew   Chang
    21 Chang
  7. Neilawattie Merna Torres
    13 Torres
  8. Yijun   Gao
    6 Gao
  9. Na Na
    1 Na
  10. Keven Muniz
    1 Muniz