title: IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase-driven tumors.
abstract: Upregulation of the ERK1 and ERK2 (ERK1/2) MAP kinase (MAPK) cascade occurs in >30% of cancers, often through mutational activation of receptor tyrosine kinases or other upstream genes, including KRAS and BRAF. Efforts to target endogenous MAPKs are challenged by the fact that these kinases are required for viability in mammals. 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. 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. MAPK scaffolds, such as IQ motif-containing GTPase activating protein 1 (IQGAP1), assemble pathway kinases to affect signal transmission, 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 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.
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.|Program in Cancer Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Katherine L
authors.initials: KL
authors.lastname: Jameson
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Pawel K
authors.initials: PK
authors.lastname: Mazur
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.|Program in Cancer Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Ashley M
authors.initials: AM
authors.lastname: Zehnder
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Jiajing
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: Zarnegar
authors.affiliation: Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA.|Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
authors.forename: Julien
authors.initials: J
authors.lastname: Sage
authors.affiliation: Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA.|Program in Cancer Biology, Stanford University School of Medicine, Stanford, California, USA.|Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Khavari
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007211:Indoles / Q000627:therapeutic use; D020935:MAP Kinase Signaling System; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009154:Mutation; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism*; D054730:Protein Interaction Domains and Motifs; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D017386:Sequence Homology, Amino Acid; D013449:Sulfonamides / Q000627:therapeutic use; D000077484:Vemurafenib; D014945:Wound Healing; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism*
chemical_list: C101203:IQ motif containing GTPase activating protein 1; D007211:Indoles; D013449:Sulfonamides; D020703:ras GTPase-Activating Proteins; D000077484:Vemurafenib; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins