title: The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer.
abstract: Advanced stages of papillary and anaplastic thyroid cancer represent a highly aggressive subset, in which there are currently few effective therapies. We and others have recently demonstrated that c-SRC is a key mediator of growth, invasion, and metastasis, and therefore represents a promising therapeutic target in thyroid cancer. However, clinically, Src inhibitor efficacy has been limited, and therefore further insights are needed to define resistance mechanisms and determine rational combination therapies. We have generated four thyroid cancer cell lines with a greater than 30-fold increase in acquired resistance to the Src inhibitor dasatinib. Upon acquisition of dasatinib resistance, the two RAS-mutant cell lines acquired the c-SRC gatekeeper mutation (T341M), whereas the two BRAF-mutant cell lines did not. Accordingly, Src signaling was refractory to dasatinib treatment in the RAS-mutant dasatinib-resistant cell lines. Interestingly, activation of the MAPK pathway was increased in all four of the dasatinib-resistant cell lines, likely due to B-Raf and c-Raf dimerization. Furthermore, MAP2K1/MAP2K2 (MEK1/2) inhibition restored sensitivity in all four of the dasatinib-resistant cell lines, and overcame acquired resistance to dasatinib in the RAS-mutant Cal62 cell line, in vivo Together, these studies demonstrate that acquisition of the c-SRC gatekeeper mutation and MAPK pathway signaling play important roles in promoting resistance to the Src inhibitor dasatinib. We further demonstrate that up-front combined inhibition with dasatinib and MEK1/2 or ERK1/2 inhibitors drives synergistic inhibition of growth and induction of apoptosis, indicating that combined inhibition may overcome mechanisms of survival in response to single-agent inhibition. Mol Cancer Ther; 15(8); 1952-63. ©2016 AACR.
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Beadnell
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Katie M
authors.initials: KM
authors.lastname: Mishall
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Qiong
authors.initials: Q
authors.lastname: Zhou
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Riffert
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Kelsey E
authors.initials: KE
authors.lastname: Wuensch
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Brittelle E
authors.initials: BE
authors.lastname: Kessler
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Maia L
authors.initials: ML
authors.lastname: Corpuz
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Xia
authors.initials: X
authors.lastname: Jing
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Jihye
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Guoliang
authors.initials: G
authors.lastname: Wang
authors.affiliation: Division of Medical Oncology, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado. University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado.
authors.forename: Aik Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado. University of Colorado Cancer Center, University of Colorado School of Medicine, Aurora, Colorado. Rebecca.Schweppe@ucdenver.edu.
authors.forename: Rebecca E
authors.initials: RE
authors.lastname: Schweppe
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D045744:Cell Line, Tumor; D000069439:Dasatinib / Q000494:pharmacology*; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D011905:Genes, ras; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D013964:Thyroid Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D019061:src-Family Kinases; D048493:Proto-Oncogene Proteins B-raf; D000069439:Dasatinib