TY - JOUR
T1 - The mitogen-activated protein kinase pathway facilitates resistance to the src inhibitor dasatinib in thyroid cancer
AU - Beadnell, Thomas C.
AU - Mishall, Katie M.
AU - Zhou, Qiong
AU - Riffert, Stephen M.
AU - Wuensch, Kelsey E.
AU - Kessler, Brittelle E.
AU - Corpuz, Maia L.
AU - Jing, Xia
AU - Kim, Jihye
AU - Wang, Guoliang
AU - Tan, Aik Choon
AU - Schweppe, Rebecca E.
N1 - Funding Information:
This work was supported by NCI grant K12-CA086913, American Cancer Society RSG-13-060-01-TBE (to R.E. Schweppe), NIH NRSA T32CA174648-01, NIH NRSA 1F31CA192805-01 (to T.C. Beadnell), NIH P50CA058187, and the Cancer League of Colorado (to A.C. Tan), and the NCI Cancer Center, grant P30CA046934. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Publisher Copyright:
©2016 American Association for Cancer Research.
PY - 2016/8
Y1 - 2016/8
N2 - 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 dasatinibresistant 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.
AB - 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 dasatinibresistant 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.
UR - http://www.scopus.com/inward/record.url?scp=84985911609&partnerID=8YFLogxK
U2 - 10.1158/1535-7163.MCT-15-0702
DO - 10.1158/1535-7163.MCT-15-0702
M3 - Article
C2 - 27222538
AN - SCOPUS:84985911609
SN - 1535-7163
VL - 15
SP - 1952
EP - 1963
JO - Molecular Cancer Therapeutics
JF - Molecular Cancer Therapeutics
IS - 8
ER -