Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents

Muling Mao, Feng Tian, John M. Mariadason, Chun C. Tsao, Robert Lemos, Farshid Dayyani, Y. N. Vashisht Gopal, Zhi Qin Jiang, Ignacio I. Wistuba, Xi M. Tang, William G. Bornman, Gideon Bollag, Gordon B. Mills, Garth Powis, Jayesh Desai, Gary E. Gallick, Michael A. Davies, Scott Kopetz

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    Abstract

    Purpose: Vemurafenib, a selective inhibitor of BRAFV600, has shown significant activity in BRAFV600 melanoma but not in less than 10% of metastatic BRAFV600 colorectal cancers (CRC), suggesting that studies of the unique hypermethylated phenotype and concurrent oncogenic activation of BRAFmut CRC may provide combinatorial strategies. Experimental Design: We conducted comparative proteomic analysis of BRAF V600E melanoma and CRC cell lines, followed by correlation of phosphoinositide 3-kinase (PI3K) pathway activation and sensitivity to the vemurafenib analogue PLX4720. Pharmacologic inhibitors and siRNA were used in combination with PLX4720 to inhibit PI3K and methyltransferase in cell lines and murine models. Results: Compared with melanoma, CRC lines show higher levels of PI3K/AKT pathway activation. CRC cell lines with mutations in PTEN or PIK3CA were less sensitive to growth inhibition by PLX4720 (P = 0.03), and knockdown of PTEN expression in sensitive CRC cells reduced growth inhibition by the drug. Combined treatment of PLX4720 with PI3K inhibitors caused synergistic growth inhibition in BRAF-mutant CRC cells with both primary and secondary resistance. In addition, methyltransferase inhibition was synergistic with PLX4720 and decreased AKT activation. In vivo, PLX4720 combined with either inhibitors of AKT or methyltransferase showed greater tumor growth inhibition than PLX4720 alone. Clones with acquired resistance to PLX4720 in vitro showed PI3K/AKT activation with EGF receptor (EGFR) or KRAS amplification. Conclusions: We show that activation of the PI3K/AKT pathway is a mechanism of both innate and acquired resistance to BRAF inhibitors in BRAFV600E CRC and suggest combinatorial approaches to improve outcomes in this poor prognosis subset of patients.

    Original languageEnglish (US)
    Pages (from-to)657-667
    Number of pages11
    JournalClinical Cancer Research
    Volume19
    Issue number3
    DOIs
    StatePublished - Feb 1 2013

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    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

    Cite this

    Mao, M., Tian, F., Mariadason, J. M., Tsao, C. C., Lemos, R., Dayyani, F., Vashisht Gopal, Y. N., Jiang, Z. Q., Wistuba, I. I., Tang, X. M., Bornman, W. G., Bollag, G., Mills, G. B., Powis, G., Desai, J., Gallick, G. E., Davies, M. A., & Kopetz, S. (2013). Resistance to BRAF inhibition in BRAF-mutant colon cancer can be overcome with PI3K inhibition or demethylating agents. Clinical Cancer Research, 19(3), 657-667. https://doi.org/10.1158/1078-0432.CCR-11-1446