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

Nature Medicine volume 19, pages 626–630 (2013)Cite this article

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Abstract

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.

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Figure 1: Diminished tumorigenesis in Iqgap1 knockout mice.
Figure 2: The ERK-binding WW domain of IQGAP1 inhibits RAS-driven invasion in human tissue.
Figure 3: Exogenous WW peptide delivery inhibits neoplastic invasion and diminishes tumorigenesis in vivo.
Figure 4: Exogenous WW peptide bypasses PLX-4032 resistance.

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Acknowledgements

We thank H. Chang, T. Oro, P. Marinkovich, D. Felsher, S. Artandi, A. Sweet-Cordero, J. Ferrell, M. Diehn, A. Wong, Z. Siprashvili, J. Reuter, A. Ungewickell, D. Webster, K. Sarin, B. Sun, C. Lee, R. Flockhart, R. Spitale, K. Wang, S. Atwood and A. Barzel for critical comments and presubmission review; N. Phillips, F. Scholl, P. Dumesic, T. Ridky, K. Grimes and D. Mochley-Rosen for helpful discussions; A. Diep for review of histologic sections; S. Tao, L. Morcom, P. Bernstein and T. Doyle and the Stanford Small Animal Imaging Facility for administrative and technical support; A. Bernards (Harvard Medical School) for providing the Iqgap1 knockout mice; and G. Fisher for helpful advice and support. This work is supported by the US Department of Veterans Affairs Office of Research and Development and US National Institutes of Health grant R01 AR49737 (P.A.K.); the Lucile Packard Foundation for Children's Health and the Leukemia and Lymphoma Society (J.S.); and the National Institutes of Health under Ruth L. Kirschstein National Research Service Award 5T32 CA09302 and the SPARK Program at Stanford (K.L.J. and A.M.Z.).

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Author notes

  1. Katherine L Jameson and Pawel K Mazur: These authors contributed equally to this work.

Authors and Affiliations

  1. Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California, USA

    Katherine L Jameson, Ashley M Zehnder, Jiajing Zhang, Brian Zarnegar & Paul A Khavari

  2. Program in Cancer Biology, Stanford University School of Medicine, Stanford, California, USA

    Katherine L Jameson, Ashley M Zehnder & Paul A Khavari

  3. Department of Pediatrics, Stanford University School of Medicine, Stanford, California, USA

    Pawel K Mazur & Julien Sage

  4. Department of Genetics, Stanford University School of Medicine, Stanford, California, USA

    Pawel K Mazur & Julien Sage

  5. Veterans Affairs Palo Alto Healthcare System, Palo Alto, California, USA

    Paul A Khavari

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  1. Katherine L Jameson
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Contributions

K.L.J. conceived the study and developed crucial proof-of-concept studies. K.L.J. also performed and designed all IQGAP1 knockout in vivo characterization, IQGAP1 RNAi tissue and cell studies, designed and constructed the WW lentivirus, performed WW peptide validation in cells, tissue and in vivo mouse models and did immunoprecipitation studies. K.L.J. contributed to PLX-4032–resistant experiments, clinical chemistry data analysis and pancreatic cancer studies. Additionally, K.L.J. coordinated all aspects of the project, interpreted data and wrote the manuscript. P.K.M. performed and designed the pancreatic cancer studies and edited the manuscript. A.M.Z. performed and designed PLX-4032–resistant experiments, contributed to cell studies, pancreatic cancer studies, bioinformatics analysis and clinical chemistry data analysis and edited the manuscript. J.Z. performed bioinformatics analysis and edited the manuscript. B.Z. performed IQGAP1 rescue experiments and contributed to immunoprecipitation studies. J.S. supervised the pancreatic cancer studies, interpreted data and helped write the manuscript. P.A.K. supervised the project, interpreted data and wrote the manuscript.

Corresponding author

Correspondence to Paul A Khavari.

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The authors declare no competing financial interests.

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Jameson, K., Mazur, P., Zehnder, A. et al. IQGAP1 scaffold-kinase interaction blockade selectively targets RAS-MAP kinase–driven tumors. Nat Med 19, 626–630 (2013). https://doi.org/10.1038/nm.3165

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