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IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase–driven tumors

2013; Nature Portfolio; Volume: 19; Issue: 5 Linguagem: Inglês

10.1038/nm.3165

1546-170X

Katherine L. Jameson, Paweł K. Mazur, Ashley Zehnder, Jiajing Zhang, Brian Zarnegar, Julien Sage, Paul A. Khavari,

PI3K/AKT/mTOR signaling in cancer

The MAPK cascade scaffolding protein IQGAP1, although dispensable for normal epithelial homeostasis, is required for RAS- and RAF-driven tumorigenesis in mouse tumor models. Accordingly, peptide-specific disruption of the interaction between IQGAP1 and ERK1/2 can bypass acquired resistance of vemurafenib-treated BRAF-mutant melanomas and extend the life span of tumor-bearing mice. Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers1, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF2. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals3,4. 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 induction2,5,6. 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 cancer7,8. MAPK scaffolds, such as IQ motif–containing GTPase activating protein 1 (IQGAP1)9,10, assemble pathway kinases to affect signal transmission11,12,13, 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-binding14 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.