Journal
NATURE MEDICINE
Volume 19, Issue 5, Pages 626-630Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/nm.3165
Keywords
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Funding
- US Department of Veterans Affairs Office of Research and Development
- US National Institutes of Health [R01 AR49737]
- Lucile Packard Foundation for Children's Health
- Leukemia and Lymphoma Society
- National Institutes of Health under Ruth L. Kirschstein National Research Service [5T32 CA09302]
- SPARK Program at Stanford
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Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers(1), often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF(2). Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals(3) (,4). Additionally, the effectiveness of new inhibitors of mutant BRAF has been diminished by acquired tumor resistance through selection for BRAF-independent mechanisms of ERK1/2 induction(2,5,6). Furthermore, recently identified ERK1/2-inducing mutations in MEK1 and MEK2 (MEK1/2) MAPK genes in melanoma confer resistance to emerging therapeutic MEK inhibitors, underscoring the challenges facing direct kinase inhibition in cancer(7,8). MAPK scaffolds, such as IQ motif-containing GTPase activating protein 1 (IQGAP1)(9,10), assemble pathway kinases to affect signal transmission(11-13), and disrupting scaffold function therefore offers an orthogonal approach to MAPK cascade inhibition. Consistent with this, we found a requirement for IQGAP1 in RAS-driven tumorigenesis in mouse and human tissue. In addition, the ERK1/2-binding(14) IQGAP1 WW domain peptide disrupted IQGAP1-ERK1/2 interactions, inhibited RAS- and RAF-driven tumorigenesis, bypassed acquired resistance to the BRAF inhibitor vemurafenib (PLX-4032) and acted as a systemically deliverable therapeutic to significantly increase the lifespan of tumor-bearing mice. Scaffold-kinase interaction blockade acts by a mechanism distinct from direct kinase inhibition and may be a strategy to target overactive oncogenic kinase cascades in cancer.
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