Inhibition of the CRAF/prohibitin interaction reverses CRAF-dependent resistance to vemurafenib.
Activating BRAF mutations promote constitutive activation of the mitogen-activated protein kinase (MAPK) signaling pathway and are common in a variety of human malignancies, including melanoma and colon cancer. Several small molecule BRAF inhibitors such as vemurafenib have been developed and demonstrate remarkable clinical efficacy. However, resistance typically emerges in most melanoma patients. Studies have demonstrated that reactivation of MAPK signaling via CRAF overexpression and dysregulation is a mechanism for vemurafenib resistance in melanoma. Prohibitins (PHBs) are highly conserved proteins that are thought to control the cell cycle, senescence and tumor suppression. PHB1 is essential for CRAF-mediated ERK1/2 activation through direct binding to CRAF. We developed a CRAF-mediated model of vemurafenib resistance in melanoma cells to assess the importance of the interaction between CRAF and PHB1 in resistance to BRAF-targeting agents. We demonstrate that CRAF overexpression renders melanoma cells resistant to BRAF-targeting agents. Moreover, treatment with the natural compound rocaglamide A disrupts the interaction between PHB and CRAF in melanoma cells, thus reducing MEK1/2 and ERK1/2 signaling, inhibiting melanoma cell growth and inducing apoptosis. The efficacy of these compounds was also demonstrated in a human melanoma xenograft model. Taken together, these data suggest that PHB1 may serve as a novel, druggable target in CRAF-mediated vemurafenib resistance.
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA.
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Doudican
The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, NY, USA.|Department of Cell Biology, New York University School of Medicine, New York, NY, USA.
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D000818:Animals; D001572:Benzofurans / Q000008:administration & dosage* / Q000494:pharmacology; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D000091402:Prohibitins; D011485:Protein Binding / Q000187:drug effects; D019908:Proto-Oncogene Proteins c-raf / Q000378:metabolism*; D012097:Repressor Proteins / Q000378:metabolism*; D013449:Sulfonamides; D000077484:Vemurafenib; D023041:Xenograft Model Antitumor Assays
D001572:Benzofurans; D007211:Indoles; C000717328:PHB protein, human; D000091402:Prohibitins; D012097:Repressor Proteins; D013449:Sulfonamides; D000077484:Vemurafenib; C107772:rocaglamide; D019908:Proto-Oncogene Proteins c-raf