Targeting extracellular matrix remodeling restores BRAF inhibitor sensitivity in BRAFi-resistant melanoma

Charles Marusak, Varsha Thakur, Yuan Li, Juliano T. Freitas, Patrick M. Zmina, Vijay S. Thakur, Mayland Chang, Ming Gao, Jiufeng Tan, Min Xiao, Yiling Lu, Gordon B. Mills, Keith Flaherty, Dennie T. Frederick, Benchun Miao, Ryan J. Sullivan, Tabea Moll, Genevieve M. Boland, Meenhard Herlyn, Gao ZhangBarbara Bedogni

    Research output: Contribution to journalArticlepeer-review

    5 Scopus citations

    Abstract

    Purpose: The extracellular matrix (ECM) is an intriguing, yet understudied component of therapy resistance. Here, we investigated the role of ECM remodeling by the collagenase, MT1-MMP, in conferring resistance of v-Raf murine sarcoma viral oncogene homolog B1 (BRAF)-mutant melanoma to BRAF inhibitor (BRAFi) therapy. Experimental Design: Publicly available RNA-sequencing data and reverse phase protein array were used to determine the relevance of MT1-MMP upregulation in BRAFi-resistant melanoma in patients, patient-derived xenografts, and cell line-derived tumors. Short hairpin RNA (shRNA)-mediated knockdown of MT1-MMP, inhibition via the selective MT1-MMP/MMP2 inhibitor, ND322, or overexpression of MT1-MMP was used to assess the role of MT1-MMP in mediating resistance to BRAFi. Results: MT1-MMP was consistently upregulated in posttreatment tumor samples derived from patients upon disease progression and in melanoma xenografts and cell lines that acquired resistance to BRAFi. shRNA- or ND322-mediated inhibition of MT1-MMP synergized with BRAFi leading to resensitization of resistant cells and tumors to BRAFi. The resistant phenotype depends on the ability of cells to cleave the ECM. Resistant cells seeded in MT1-MMP uncleavable matrixes were resensitized to BRAFi similarly to MT1-MMP inhibition. This is due to the inability of cells to activate integrinb1 (ITGB1)/FAK signaling, as restoration of ITGB1 activity is sufficient to maintain resistance to BRAFi in the context of MT1-MMP inhibition. Finally, the increase in MT1-MMP in BRAFi-resistant cells is TGFb dependent, as inhibition of TGFb receptors I/II dampens MT1-MMP overexpression and restores sensitivity to BRAF inhibition. Conclusions: BRAF inhibition results in a selective pressure toward higher expression of MT1-MMP. MT1-MMP is pivotal to an ECM-based signaling pathway that confers resistance to BRAFi therapy.

    Original languageEnglish (US)
    Pages (from-to)6039-6050
    Number of pages12
    JournalClinical Cancer Research
    Volume26
    Issue number22
    DOIs
    StatePublished - Nov 15 2020

    ASJC Scopus subject areas

    • Oncology
    • Cancer Research

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