Reference Detail

Ref Type

Journal Article

PMID

(27222538)

Authors

Beadnell TC, Mishall KM, Zhou Q, Riffert SM, Wuensch KE, Kessler BE, Corpuz ML, Jing X, Kim J, Wang G, Tan AC, Schweppe RE

Title

The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer.

Journal	Vol	Issue	Date	Pages	Journal Short Title
Molecular cancer therapeutics	15	8	2016 Aug	1952-63	Mol Cancer Ther

URL

Abstract Text

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.

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Molecular Profile	Treatment Approach

Gene Name	Source	Synonyms	Protein Domains	Gene Description	Gene Role

Therapy Name	Drugs	Efficacy Evidence	Clinical Trials

Drug Name	Trade Name	Synonyms	Drug Classes	Drug Description

Gene	Variant	Impact	Protein Effect	Variant Description	Associated with drug Resistance

Molecular Profile	Indication/Tumor Type	Response Type	Therapy Name	Approval Status	Evidence Type	Efficacy Evidence	References
BRAF V600E	thyroid cancer	sensitive	Dasatinib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) and Koselugo (selumetinib) synergistically inhibited proliferation and induced apoptosis in both parental thyroid cancer cell lines harboring BRAF V600E and those acquired Sprycel (dasatinib)-resistance in culture (PMID: 27222538).	27222538
HRAS G13R	thyroid cancer	sensitive	Dasatinib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) and Mekinist (trametinib) synergistically inhibited growth and induced apoptosis in a thyroid cancer cell line harboring HRAS G13R in culture (PMID: 27222538).	27222538
BRAF V600E	thyroid cancer	sensitive	Dasatinib + Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) and Mekinist (trametinib) synergistically inhibited proliferation and induced apoptosis in both parental thyroid cancer cell lines harboring BRAF V600E and those acquired Sprycel (dasatinib)-resistance in culture (PMID: 27222538).	27222538
HRAS G13R	thyroid cancer	sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of a thyroid cancer cell line harboring HRAS G13R in culture (PMID: 27222538).	27222538
BRAF V600E	thyroid cancer	sensitive	Dasatinib + SCH772984	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) and SCH772984 synergistically inhibited proliferation and induced apoptosis in both parental thyroid cancer cell lines harboring BRAF V600E and those acquired Sprycel (dasatinib)-resistance in culture (PMID: 27222538).	27222538
BRAF V600E	thyroid cancer	sensitive	Selumetinib	Preclinical - Cell line xenograft	Actionable	In a preclinical study, Selumetinib (AZD6244) inhibited growth of both parental thyroid cancer cell lines harboring BRAF V600E and those acquired Sprycel (dasatinib)-resistance in culture (PMID: 27222538).	27222538
BRAF V600E	thyroid cancer	predicted - sensitive	Trametinib	Preclinical - Cell culture	Actionable	In a preclinical study, Mekinist (trametinib) inhibited growth of both parental thyroid cancer cell lines harboring BRAF V600E and those acquired Sprycel (dasatinib)-resistance in culture (PMID: 27222538).	27222538
HRAS G13R	thyroid cancer	sensitive	Dasatinib + Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Sprycel (dasatinib) and Koselugo (selumetinib) synergistically inhibited growth and induced apoptosis in a thyroid cancer cell line harboring HRAS G13R in culture (PMID: 27222538).	27222538
HRAS G13R	thyroid cancer	sensitive	Selumetinib	Preclinical - Cell culture	Actionable	In a preclinical study, Selumetinib (AZD6244) inhibited growth of a thyroid cancer cell line harboring HRAS G13R in culture (PMID: 27222538).	27222538