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Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
07:49

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Published on: July 17, 2019

Mechanism of MEK inhibition determines efficacy in mutant KRAS- versus BRAF-driven cancers

Georgia Hatzivassiliou1, Jacob R Haling, Huifen Chen

  • 1Department of Translational Oncology, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA. hatzivassiliou.georgia@gene.com

Nature
|August 13, 2013
PubMed

Insights

Targeting the MAPK pathway with MEK inhibitors shows promise for KRAS and BRAF-mutant cancers. Different MEK inhibitor strategies are needed for optimal efficacy in KRAS-mutant versus BRAF-mutant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Activating mutations in KRAS and BRAF drive cancer by constantly activating the MAPK pathway.
  • MEK inhibitors targeting MAPK signaling are in clinical trials for these cancers, showing success in BRAF-mutant melanoma but less in KRAS-mutant disease.

Purpose of the Study:

  • To investigate the distinct mechanisms of MEK activation in KRAS-mutant versus BRAF-mutant tumors.
  • To identify genotype-specific inhibition strategies for optimal anti-tumor activity.

Main Methods:

  • Structural and functional analysis of MEK inhibitors (GDC-0623, G-573, GDC-0973/cobimetinib).
  • Evaluation of inhibitor efficacy in preclinical models of KRAS-mutant and BRAF-mutant cancers.

Main Results:

  • MEK inhibitors GDC-0623 and G-573 show efficacy in KRAS-driven tumors by forming a key hydrogen bond with S212, blocking feedback phosphorylation.
  • MEK inhibitor GDC-0973 (cobimetinib) demonstrates superior efficacy in BRAF-mutant tumors by potently inhibiting active, phosphorylated MEK.

Conclusions:

  • Distinct MEK activation states in KRAS- vs. BRAF-mutant tumors necessitate tailored inhibitor designs.
  • Targeting these distinct activation states offers a strategy to improve therapeutic index and clinical response in patients.

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