title: Targeting BMK1 Impairs the Drug Resistance to Combined Inhibition of BRAF and MEK1/2 in Melanoma.
abstract: Combined inhibition of BRAF and MEK1/2 (CIBM) improves therapeutic efficacy of BRAF-mutant melanoma. However, drug resistance to CIBM is inevitable and the drug resistance mechanisms still remain to be elucidated. Here, we show that BMK1 pathway contributes to the drug resistance to CIBM. Considering that ERK1/2 pathway regulates cellular processes by phosphorylating, we first performed a SILAC phosphoproteomic profiling of CIBM. Phosphorylation of 239 proteins was identified to be downregulated, while phosphorylation of 47 proteins was upregulated. Following siRNA screening of 47 upregulated proteins indicated that the knockdown of BMK1 showed the most significant ability to inhibit the proliferation of CIBM resistant cells. It was found that phosphorylation of BMK1 was enhanced in resistant cells, which suggested an association of BMK1 with drug resistance. Further study indicated that phospho-activation of BMK1 by MEK5D enhanced the resistance to CIBM. Conversely, inhibition of BMK1 by shRNAi or BMK1 inhibitor (XMD8-92) impaired not only the acquirement of resistance to CIBM, but also the proliferation of CIBM resistant cells. Further kinome-scale siRNA screening demonstrated that SRC\MEK5 cascade promotes the phospho-activation of BMK1 in response to CIBM. Our study not only provides a global phosphoproteomic view of CIBM in melanoma, but also demonstrates that inhibition of BMK1 has therapeutic potential for the treatment of melanoma.
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, DaLian Medical University, 9 Western Lvshun South Road, Dalian, Liaoning 116044, China.
authors.forename: Chengli
authors.initials: C
authors.lastname: Song
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, DaLian Medical University, 9 Western Lvshun South Road, Dalian, Liaoning 116044, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Wang
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, DaLian Medical University, 9 Western Lvshun South Road, Dalian, Liaoning 116044, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, DaLian Medical University, 9 Western Lvshun South Road, Dalian, Liaoning 116044, China.
authors.forename: Kai
authors.initials: K
authors.lastname: Wang
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, DaLian Medical University, 9 Western Lvshun South Road, Dalian, Liaoning 116044, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xie
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, DaLian Medical University, 9 Western Lvshun South Road, Dalian, Liaoning 116044, China.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, DaLian Medical University, 9 Western Lvshun South Road, Dalian, Liaoning 116044, China.
authors.forename: Kui
authors.initials: K
authors.lastname: Jiang
authors.affiliation: Shanghai Key Laboratory of Regulatory Biology, School of Life Sciences, East China Normal University, Shanghai, 200241, China.
authors.forename: Lujian
authors.initials: L
authors.lastname: Liao
authors.affiliation: Department of Chemical Physiology, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: John R
authors.initials: JR
authors.lastname: Yates
authors.affiliation: Department of Immunology and Microbial Science, The Scripps Research Institute, 10550 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Jiing-Dwan
authors.initials: JD
authors.lastname: Lee
authors.affiliation: Department of Oncology, Second Affiliated Hospital, Institute of Cancer Stem Cell, DaLian Medical University, 9 Western Lvshun South Road, Dalian, Liaoning 116044, China.
authors.forename: Qingkai
authors.initials: Q
authors.lastname: Yang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019008:Drug Resistance, Neoplasm; D020868:Gene Silencing; D005820:Genetic Testing; D006801:Humans; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors*; D048370:MAP Kinase Kinase 2 / Q000037:antagonists & inhibitors*; D008545:Melanoma / Q000188:drug therapy*; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors*; D008954:Models, Biological; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; C482128:MAP2K2 protein, human; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D048054:Mitogen-Activated Protein Kinase 7; D048369:MAP Kinase Kinase 1; D048370:MAP Kinase Kinase 2; C482125:MAP2K1 protein, human