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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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References

  1. Downward, J. Targeting RAS signalling pathways in cancer therapy. Nat. Rev. Cancer 3, 11–22 (2003).

    Article  CAS  Google Scholar 

  2. McCormick, F. Cancer therapy based on oncogene addiction. J. Surg. Oncol. 103, 464–467 (2011).

    Article  CAS  Google Scholar 

  3. Scholl, F.A. et al. MEK1/2 MAPK kinases are essential for mammalian development, homeostasis, and Raf-induced hyperplasia. Dev. Cell 12, 615–629 (2007).

    Article  CAS  Google Scholar 

  4. Dumesic, P.A., Scholl, F.A., Barragan, D.I. & Khavari, P.A. ERK1/2 MAP kinases are required for epidermal G2/M progression. J. Cell Biol. 185, 409–422 (2009).

    Article  CAS  Google Scholar 

  5. Nazarian, R. et al. Melanomas acquire resistance to B-RAFV600E inhibition by RTK or N-RAS upregulation. Nature 468, 973–977 (2010).

    Article  CAS  Google Scholar 

  6. Johannessen, C.M. et al. COT drives resistance to RAF inhibition through MAP kinase pathway reactivation. Nature 468, 968–972 (2010).

    Article  CAS  Google Scholar 

  7. Nikolaev, S.I. et al. Exome sequencing identifies recurrent somatic MAP2K1 and MAP2K2 mutations in melanoma. Nat. Genet. 44, 133–139 (2012).

    Article  CAS  Google Scholar 

  8. Wagle, N. et al. Dissecting therapeutic resistance to RAF inhibition in melanoma by tumor genomic profiling. J. Clin. Oncol. 29, 3085–3096 (2011).

    Article  CAS  Google Scholar 

  9. White, C.D., Brown, M.D. & Sacks, D.B. IQGAPs in cancer: a family of scaffold proteins underlying tumorigenesis. FEBS Lett. 583, 1817–1824 (2009).

    Article  CAS  Google Scholar 

  10. Johnson, M., Sharma, M. & Henderson, B.R. IQGAP1 regulation and roles in cancer. Cell Signal. 21, 1471–1478 (2009).

    Article  CAS  Google Scholar 

  11. Kolch, W. Coordinating ERK/MAPK signalling through scaffolds and inhibitors. Nat. Rev. Mol. Cell Biol. 6, 827–837 (2005).

    Article  CAS  Google Scholar 

  12. Ferrell, J.E. Jr. What do scaffold proteins really do? Sci. STKE 2000, pe1 (2000).

    Article  Google Scholar 

  13. Good, M.C., Zalatan, J.G. & Lim, W.A. Scaffold proteins: hubs for controlling the flow of cellular information. Science 332, 680–686 (2011).

    Article  CAS  Google Scholar 

  14. Roy, M., Li, Z. & Sacks, D.B. IQGAP1 binds ERK2 and modulates its activity. J. Biol. Chem. 279, 17329–17337 (2004).

    Article  CAS  Google Scholar 

  15. White, C.D., Erdemir, H.H. & Sacks, D.B. IQGAP1 and its binding proteins control diverse biological functions. Cell Signal. 24, 826–834 (2012).

    Article  CAS  Google Scholar 

  16. Clark, E.A., Golub, T.R., Lander, E.S. & Hynes, R.O. Genomic analysis of metastasis reveals an essential role for RhoC. Nature 406, 532–535 (2000).

    Article  CAS  Google Scholar 

  17. Jadeski, L., Mataraza, J.M., Jeong, H.W., Li, Z. & Sacks, D.B. IQGAP1 stimulates proliferation and enhances tumorigenesis of human breast epithelial cells. J. Biol. Chem. 283, 1008–1017 (2008).

    Article  CAS  Google Scholar 

  18. Liu, Z. et al. IQGAP1 plays an important role in the invasiveness of thyroid cancer. Clin. Cancer Res. 16, 6009–6018 (2010).

    Article  CAS  Google Scholar 

  19. Sato, A. et al. Association of RNase L with a RAS GTPase-activating-like protein IQGAP1 in mediating the apoptosis of a human cancer cell-line. FEBS J. 277, 4464–4473 (2010).

    Article  CAS  Google Scholar 

  20. Li, S., Wang, Q., Chakladar, A., Bronson, R.T. & Bernards, A. Gastric hyperplasia in mice lacking the putative Cdc42 effector IQGAP1. Mol. Cell Biol. 20, 697–701 (2000).

    Article  CAS  Google Scholar 

  21. Fujiki, H. et al. Codon 61 mutations in the c-Harvey-RAS gene in mouse skin tumors induced by 7,12-dimethylbenz[a]anthracene plus okadaic acid class tumor promoters. Mol. Carcinog. 2, 184–187 (1989).

    Article  CAS  Google Scholar 

  22. Tarutani, M., Cai, T., Dajee, M. & Khavari, P.A. Inducible activation of RAS and Raf in adult epidermis. Cancer Res. 63, 319–323 (2003).

    CAS  PubMed  Google Scholar 

  23. Reuter, J.A. et al. Modeling inducible human tissue neoplasia identifies an extracellular matrix interaction network involved in cancer progression. Cancer Cell 15, 477–488 (2009).

    Article  CAS  Google Scholar 

  24. Nabeshima, K., Shimao, Y., Inoue, T. & Koono, M. Immunohistochemical analysis of IQGAP1 expression in human colorectal carcinomas: its overexpression in carcinomas and association with invasion fronts. Cancer Lett. 176, 101–109 (2002).

    Article  CAS  Google Scholar 

  25. Sugimoto, N. et al. IQGAP1, a negative regulator of cell-cell adhesion, is upregulated by gene amplification at 15q26 in gastric cancer cell lines HSC39 and 40A. J. Hum. Genet. 46, 21–25 (2001).

    Article  CAS  Google Scholar 

  26. Hingorani, S.R. et al. Preinvasive and invasive ductal pancreatic cancer and its early detection in the mouse. Cancer Cell 4, 437–450 (2003).

    Article  CAS  Google Scholar 

  27. Collins, M.A. et al. Oncogenic KRAS is required for both the initiation and maintenance of pancreatic cancer in mice. J. Clin. Invest. 122, 639–653 (2012).

    Article  CAS  Google Scholar 

  28. Ridky, T.W., Chow, J.M., Wong, D.J. & Khavari, P.A. Invasive three-dimensional organotypic neoplasia from multiple normal human epithelia. Nat. Med. 16, 1450–1455 (2010).

    Article  CAS  Google Scholar 

  29. Roy, M., Li, Z. & Sacks, D.B. IQGAP1 is a scaffold for mitogen-activated protein kinase signaling. Mol. Cell Biol. 25, 7940–7952 (2005).

    Article  CAS  Google Scholar 

  30. Rothbard, J.B. et al. Conjugation of arginine oligomers to cyclosporin A facilitates topical delivery and inhibition of inflammation. Nat. Med. 6, 1253–1257 (2000).

    Article  CAS  Google Scholar 

  31. Jackson, E.L. et al. Analysis of lung tumor initiation and progression using conditional expression of oncogenic K-RAS. Genes Dev. 15, 3243–3248 (2001).

    Article  CAS  Google Scholar 

  32. Kawaguchi, Y. et al. The role of the transcriptional regulator Ptf1a in converting intestinal to pancreatic progenitors. Nat. Genet. 32, 128–134 (2002).

    Article  CAS  Google Scholar 

  33. Marino, S., Vooijs, M., van Der Gulden, H., Jonkers, J. & Berns, A. Induction of medulloblastomas in p53-null mutant mice by somatic inactivation of Rb in the external granular layer cells of the cerebellum. Genes Dev. 14, 994–1004 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Toftgard, R., Roop, D.R. & Yuspa, S.H. Proto-oncogene expression during two-stage carcinogenesis in mouse skin. Carcinogenesis 6, 655–657 (1985).

    Article  CAS  Google Scholar 

  35. Olive, K.P. et al. Inhibition of Hedgehog signaling enhances delivery of chemotherapy in a mouse model of pancreatic cancer. Science 324, 1457–1461 (2009).

    Article  CAS  Google Scholar 

Download references

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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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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