MEK Inhibition Overcomes Cisplatin Resistance Conferred by SOS/MAPK Pathway Activation in Squamous Cell Carcinoma.
Genomic analyses of squamous cell carcinoma (SCC) have yet to yield significant strategies against pathway activation to improve treatment. Platinum-based chemotherapy remains the mainstay of treatment for SCC of different histotypes either as a single-agent or alongside other chemotherapeutic drugs or radiotherapy; however, resistance inevitably emerges, which limits the duration of treatment response. To elucidate mechanisms that mediate resistance to cisplatin, we compared drug-induced perturbations to gene and protein expression between cisplatin-sensitive and -resistant SCC cells, and identified MAPK-ERK pathway upregulation and activation in drug-resistant cells. ERK-induced resistance appeared to be activated by Son of Sevenless (SOS) upstream, and mediated through Bim degradation downstream. Clinically, elevated p-ERK expression was associated with shorter disease-free survival in patients with locally advanced head and neck SCC treated with concurrent chemoradiation. Inhibition of MEK/ERK, but not that of EGFR or RAF, augmented cisplatin sensitivity in vitro and demonstrated efficacy and tolerability in vivo. Collectively, these findings suggest that inhibition of the activated SOS-MAPK-ERK pathway may augment patient responses to cisplatin treatment.
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Li Ren
LR
Kong
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Kian Ngiap
KN
Chua
Institute of Molecular and Cell Biology, A*STAR, Singapore.
Wen Jing
WJ
Sim
Institute of Molecular and Cell Biology, A*STAR, Singapore.
Hsien Chun
HC
Ng
Cancer Science Institute of Singapore, National University of Singapore, Singapore.
Chonglei
C
Bi
Department of Hematology-Oncology, National University Hospital, Singapore. National University Cancer Institute, Singapore.
Jingshan
J
Ho
Department of Pathology, National University Hospital, Singapore.
Min En
ME
Nga
Department of Pathology, National University Hospital, Singapore.
Yin Huei
YH
Pang
National Cancer Centre, Singapore.
Weijie Richard
WR
Ong
Cancer Science Institute of Singapore, National University of Singapore, Singapore. Department of Hematology-Oncology, National University Hospital, Singapore. National University Cancer Institute, Singapore.
Ross Andrew
RA
Soo
National Cancer Centre, Singapore.
Hung
H
Huynh
Cancer Science Institute of Singapore, National University of Singapore, Singapore. Department of Hematology-Oncology, National University Hospital, Singapore. National University Cancer Institute, Singapore.
Wee Joo
WJ
Chng
Cancer Science Institute of Singapore, National University of Singapore, Singapore. Institute of Molecular and Cell Biology, A*STAR, Singapore. Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore.
Jean-Paul
JP
Thiery
Cancer Science Institute of Singapore, National University of Singapore, Singapore. Department of Hematology-Oncology, National University Hospital, Singapore. National University Cancer Institute, Singapore. phcgbc@nus.edu.sg.
Boon Cher
BC
Goh
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D000072224:Bcl-2-Like Protein 11; D001549:Benzamides / Q000494:pharmacology; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D002945:Cisplatin / Q000494:pharmacology*; D004159:Diphenylamine / Q000031:analogs & derivatives / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D016513:Mice, SCID; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics / Q000379:methods; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D020664:Son of Sevenless Proteins / Q000235:genetics / Q000378:metabolism*; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C000606775:BCL2L11 protein, human; D000072224:Bcl-2-Like Protein 11; C000606776:Bcl2l11 protein, mouse; D001549:Benzamides; D008565:Membrane Proteins; D011518:Proto-Oncogene Proteins; D020664:Son of Sevenless Proteins; C506614:mirdametinib; D004159:Diphenylamine; D020929:Mitogen-Activated Protein Kinase Kinases; D002945:Cisplatin