Inhibition of YAP function overcomes BRAF inhibitor resistance in melanoma cancer stem cells
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Matthew L. Fisher1, Daniel Grun1, Gautam Adhikary1, Wen Xu1 and Richard L. Eckert1,2,3,4
1Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
2Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
3Department of Reproductive Biology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
4The Marlene and Stewart Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA
Richard L. Eckert, email: firstname.lastname@example.org
Keywords: melanoma; YAP and TAZ; cancer stem cell; BRAF inhibitor; drug resistance
Received: September 26, 2017 Accepted: October 25, 2017 Published: November 22, 2017
Treating BRAF inhibitor-resistant melanoma is an important therapeutic goal. Thus, it is important to identify and target mechanisms of resistance to improve therapy. The YAP1 and TAZ proteins of the Hippo signaling pathway are important drivers of cancer cell survival, and are BRAF inhibitor resistant factors in melanoma. We examine the role of YAP1/TAZ in melanoma cancer stem cells (MCS cells). We demonstrate that YAP1, TAZ and TEAD (TEA domain transcription factor) levels are elevated in BRAF inhibitor resistant MCS cells and enhance cell survival, spheroid formation, matrigel invasion and tumor formation. Moreover, increased YAP1, TAZ and TEAD are associated with sustained ERK1/2 activity that is not suppressed by BRAF inhibitor. Xenograft studies show that treating BRAF inhibitor-resistant tumors with verteporfin, an agent that interferes with YAP1 function, reduces YAP1/TAZ level, restores BRAF inhibitor suppression of ERK1/2 signaling and reduces tumor growth. Verteporfin is highly effective as concentrations of verteporfin that do not impact tumor formation restore BRAF inhibitor suppression of tumor formation, suggesting that co-treatment with agents that inhibit YAP1 and BRAF(V600E) may be a viable therapy for cancer stem cell-derived BRAF inhibitor-resistant melanoma.
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