LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients

Yu Jin Kim; Sungyoul Hong; Minjung Sung; Min Jeong Park; Kyungsoo Jung; Ka-Won Noh; Doo-Yi Oh; Mi-Sook Lee; Ensel Oh; Young Kee Shin; Yoon-La Choi

doi:10.18632/oncotarget.12657

LYN expression predicts the response to dasatinib in a subpopulation of lung adenocarcinoma patients

Oncotarget. 2016 Dec 13;7(50):82876-82888. doi: 10.18632/oncotarget.12657.

Authors

Yu Jin Kim¹, Sungyoul Hong², Minjung Sung¹, Min Jeong Park², Kyungsoo Jung^{1

3}, Ka-Won Noh^{1

3}, Doo-Yi Oh^{1

3}, Mi-Sook Lee^{1

3}, Ensel Oh^{1

3}, Young Kee Shin^{2

4}, Yoon-La Choi^{1

3

5}

Affiliations

¹ Laboratory of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
² Laboratory of Molecular Pathology and Cancer Genomics, Department of Pharmacy, College of Pharmacy, Seoul National University, Seoul, Korea.
³ Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
⁴ The Center for Anti-cancer Companion Diagnostics, Bio-MAX/N-Bio, Seoul National University, Seoul, Korea.
⁵ Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.

Abstract

Therapies targeting SRC family kinases (SFKs) have shown efficacy in treating non-small cell lung cancer (NSCLC). However, recent clinical trials have found that the SFK inhibitor dasatinib is ineffective in some patient cohorts. Regardless, dasatinib treatment may benefit some NSCLC patient subgroups. Here, we investigated whether expression of LYN, a member of the SFK family, is associated with patient survival, the efficacy of dasatinib, and/or NSCLC cell viability. LYN expression was associated with poor overall survival in a multivariate analysis, and this association was strongest in non-smoker female patients with adenocarcinoma (ADC). In lung ADC cells, LYN expression enhanced cell proliferation, migration, and invasion. Dasatinib inhibited LYN activity and decreased cell viability in LYN-positive ADC cell lines and xenografts. Additionally, we identified the SFKs SRC and YES as candidate dasatinib targets in LYN-negative ADC cell lines. Our findings suggest that LYN is a useful prognostic marker and a selective target of dasatinib therapy in the lung ADC subpopulation especially in female non-smokers with lung ADC.

Keywords: LYN; SRC; YES; dasatinib; lung adenocarcinoma subgroup.

MeSH terms

Adenocarcinoma / drug therapy*
Adenocarcinoma / enzymology
Adenocarcinoma / mortality
Adenocarcinoma / pathology
Adenocarcinoma of Lung
Adult
Aged
Aged, 80 and over
Antineoplastic Agents / therapeutic use*
Biomarkers, Tumor / antagonists & inhibitors*
Biomarkers, Tumor / genetics
Biomarkers, Tumor / metabolism
Carcinoma, Non-Small-Cell Lung / drug therapy*
Carcinoma, Non-Small-Cell Lung / enzymology
Carcinoma, Non-Small-Cell Lung / mortality
Carcinoma, Non-Small-Cell Lung / pathology
Cell Line, Tumor
Cell Movement / drug effects
Cell Proliferation / drug effects
Cell Survival / drug effects
Dasatinib / therapeutic use*
Female
Humans
Kaplan-Meier Estimate
Lung Neoplasms / drug therapy*
Lung Neoplasms / enzymology
Lung Neoplasms / mortality
Lung Neoplasms / pathology
Male
Middle Aged
Multivariate Analysis
Neoplasm Invasiveness
Proportional Hazards Models
Protein Kinase Inhibitors / therapeutic use*
Risk Factors
Sex Factors
Smoking / adverse effects
Time Factors
Treatment Outcome
Xenograft Model Antitumor Assays
Young Adult
src-Family Kinases / antagonists & inhibitors*
src-Family Kinases / genetics
src-Family Kinases / metabolism

Substances

Antineoplastic Agents
Biomarkers, Tumor
Protein Kinase Inhibitors
lyn protein-tyrosine kinase
src-Family Kinases
Dasatinib