An inhibitor of the pleckstrin homology domain of CNK1 selectively blocks the growth of mutant KRAS cells and tumors

Martin Indarte, Roisin Puentes, Marco Maruggi, Nathan T. Ihle, Geoffrey Grandjean, Michael Scott, Zamal Ahmed, Emmanuelle J. Meuillet, Shuxing Zang, Robert Lemos, Lei Du-Cuny, Fabiana I.A.L. Layng, Ricardo G. Correa, Laurie A. Bankston, Robert C. Liddington, Lynn Kirkpatrick, Garth Powis

Research output: Contribution to journalArticle

Abstract

Cnk1 (connector enhancer of kinase suppressor of Ras 1) is a pleckstrin homology (PH) domain-containing scaffold protein that increases the efficiency of Ras signaling pathways, imparting efficiency and specificity to the response of cell proliferation, survival, and migration. Mutated KRAS (mut-KRAS) is the most common proto-oncogenic event, occurring in approximately 25% of human cancers and has no effective treatment. In this study, we show that selective inhibition of Cnk1 blocks growth and Raf/Mek/Erk, Rho and RalA/B signaling in mut-KRAS lung and colon cancer cells with little effect on wild-type (wt)-KRAS cells. Cnk1 inhibition decreased anchorage-independent mut-KRas cell growth more so than growth on plastic, without the partial "addiction" to mut-KRAS seen on plastic. The PH domain of Cnk1 bound with greater affinity to PtdIns(4,5)P2 than PtdIns(3,4,5)P3, and Cnk1 localized to areas of the plasma membranes rich in PtdIns, suggesting a role for the PH domain in the biological activity of Cnk1. Through molecular modeling and structural modification, we identified a compound PHT-7.3 that bound selectively to the PH domain of Cnk1, preventing plasma membrane colocalization with mut-KRas. PHT-7.3 inhibited mut-KRas, but not wild-type KRas cancer cell and tumor growth and signaling. Thus, the PH domain of Cnk1 is a druggable target whose inhibition selectively blocks mutant KRas activation, making Cnk1 an attractive therapeutic target in patients with mut-KRAS-driven cancer.

Original languageEnglish (US)
Pages (from-to)3100-3111
Number of pages12
JournalCancer Research
Volume79
Issue number12
DOIs
StatePublished - Jun 15 2019

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Indarte, M., Puentes, R., Maruggi, M., Ihle, N. T., Grandjean, G., Scott, M., Ahmed, Z., Meuillet, E. J., Zang, S., Lemos, R., Du-Cuny, L., Layng, F. I. A. L., Correa, R. G., Bankston, L. A., Liddington, R. C., Kirkpatrick, L., & Powis, G. (2019). An inhibitor of the pleckstrin homology domain of CNK1 selectively blocks the growth of mutant KRAS cells and tumors. Cancer Research, 79(12), 3100-3111. https://doi.org/10.1158/0008-5472.CAN-18-2372