Fisher Matthew L, Grun Daniel, Adhikary Gautam, Xu Wen, Eckert Richard L
Department of Biochemistry and Molecular Biology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA.
Department of Dermatology, University of Maryland School of Medicine, Baltimore, Maryland, 21201, USA.
Oncotarget. 2017 Nov 22;8(66):110257-110272. doi: 10.18632/oncotarget.22628. eCollection 2017 Dec 15.
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.
治疗对BRAF抑制剂耐药的黑色素瘤是一个重要的治疗目标。因此，识别并靶向耐药机制以改善治疗效果至关重要。Hippo信号通路中的YAP1和TAZ蛋白是癌细胞存活的重要驱动因素，也是黑色素瘤中BRAF抑制剂的耐药因子。我们研究了YAP1/TAZ在黑色素瘤癌干细胞（MCS细胞）中的作用。我们证明，在对BRAF抑制剂耐药的MCS细胞中，YAP1、TAZ和TEAD（TEA结构域转录因子）水平升高，并增强细胞存活、球体形成、基质胶侵袭和肿瘤形成。此外，YAP1、TAZ和TEAD的增加与持续的ERK1/2活性相关，而BRAF抑制剂无法抑制这种活性。异种移植研究表明，用干扰YAP1功能的维替泊芬治疗对BRAF抑制剂耐药的肿瘤，可降低YAP1/TAZ水平，恢复BRAF抑制剂对ERK1/2信号的抑制，并减少肿瘤生长。维替泊芬非常有效，因为不影响肿瘤形成的维替泊芬浓度可恢复BRAF抑制剂对肿瘤形成的抑制，这表明联合使用抑制YAP1和BRAF（V600E）的药物可能是治疗癌干细胞来源的对BRAF抑制剂耐药的黑色素瘤的一种可行疗法。
