TY - JOUR
T1 - Epithelial-mesenchymal transition predicts polo-like kinase 1 inhibitor-mediated apoptosis in non-small cell lung cancer
AU - Ferrarotto, Renata
AU - Goonatilake, Ruchitha
AU - Yoo, Suk Young
AU - Tong, Pan
AU - Giri, Uma
AU - Peng, Shaohua
AU - Minna, John
AU - Girard, Luc
AU - Wang, Yuehong
AU - Wang, Liguang
AU - Li, Lerong
AU - Diao, Lixia
AU - Peng, David H.
AU - Gibbons, Don L.
AU - Glisson, Bonnie S.
AU - Heymach, John V.
AU - Wang, Jing
AU - Byers, Lauren A.
AU - Johnson, Faye M.
N1 - Funding Information:
This work was supported by The Lung Cancer Research Foundation (to F.M. Johnson) and The University of Texas MD Anderson Cancer Center Lung Cancer Moon Shot (to J.V. Heymach). Reverse-phase protein arrays and flow cytometry were supported by the NIH/NCI under award number P30CA016672 (to MD Anderson Cancer Center, Houston, TX). The gene expression and mutational profiles of the NSCLC lines were previously generated as part of the UT SPORE in Lung Cancer (5-P50-CA090907-15). D.H. Peng was supported by Cancer Prevention and Research Institute of Texas Training Grant RP140106. D.L. Gibbons was supported by NCI grant K08-CA151651, the MD Anderson Physician Scientist Award, and Rexanna's Foundation for Fighting Lung Cancer and is an R. Lee Clark Fellow of MD Anderson supported by the Jeanne F. Shelby Scholarship Fund. Bioinformatic analysis also was supported under award number P30CA016672.
Publisher Copyright:
© 2015 American Association for Cancer Research.
PY - 2016/4/1
Y1 - 2016/4/1
N2 - Purpose: To identify new therapeutic targets for non-small cell lung cancer (NSCLC), we systematically searched two cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development. Experimental Design: To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor-induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using three PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines. Results: The NSCLC cell lines had different sensitivities to PLK1 inhibition, with a minority demonstrating sensitivity to all three inhibitors. PLK1 inhibition led to G2-M arrest, but only treatment-sensitive cell lines underwent substantial apoptosis following PLK1 inhibition. NSCLC lines with high epithelial-mesenchymal transition (EMT) gene signature scores (mesenchymal cell lines) were more sensitive to PLK1 inhibition than epithelial lines (P < 0.02). Likewise, proteomic profiling demonstrated that E-cadherin expression was higher in the resistant cell lines than in the sensitive ones (P < 0.01). Induction of an epithelial phenotype by expression of the miRNA miR-200 increased cellular resistance to PLK1 inhibition. Also, KRAS mutation and alterations in the tight-junction, ErbB, and Rho signaling pathways correlated with drug response of NSCLC. Conclusions: In this first reported large-scale integrated analysis of PLK1 inhibitor sensitivity, we demonstrated that EMT leads to PLK1 inhibition sensitivity of NSCLC cells. Our findings have important clinical implications for mesenchymal NSCLC, a significant subtype of the disease that is associated with resistance to currently approved targeted therapies. Clin Cancer Res; 22(7); 1674-86.
AB - Purpose: To identify new therapeutic targets for non-small cell lung cancer (NSCLC), we systematically searched two cancer cell line databases for sensitivity data on a broad range of drugs. We identified polo-like kinase 1 (PLK1) as the most promising target for further investigation based on a subset of sensitive NSCLC cell lines and inhibitors that were in advanced clinical development. Experimental Design: To identify potential biomarkers of response of NSCLC to PLK1 inhibition and mechanisms of PLK1 inhibitor-induced apoptosis, integrated analysis of gene and protein expression, gene mutations, and drug sensitivity was performed using three PLK1 inhibitors (volasertib, BI2536, and GSK461364) with a large panel of NSCLC cell lines. Results: The NSCLC cell lines had different sensitivities to PLK1 inhibition, with a minority demonstrating sensitivity to all three inhibitors. PLK1 inhibition led to G2-M arrest, but only treatment-sensitive cell lines underwent substantial apoptosis following PLK1 inhibition. NSCLC lines with high epithelial-mesenchymal transition (EMT) gene signature scores (mesenchymal cell lines) were more sensitive to PLK1 inhibition than epithelial lines (P < 0.02). Likewise, proteomic profiling demonstrated that E-cadherin expression was higher in the resistant cell lines than in the sensitive ones (P < 0.01). Induction of an epithelial phenotype by expression of the miRNA miR-200 increased cellular resistance to PLK1 inhibition. Also, KRAS mutation and alterations in the tight-junction, ErbB, and Rho signaling pathways correlated with drug response of NSCLC. Conclusions: In this first reported large-scale integrated analysis of PLK1 inhibitor sensitivity, we demonstrated that EMT leads to PLK1 inhibition sensitivity of NSCLC cells. Our findings have important clinical implications for mesenchymal NSCLC, a significant subtype of the disease that is associated with resistance to currently approved targeted therapies. Clin Cancer Res; 22(7); 1674-86.
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U2 - 10.1158/1078-0432.CCR-14-2890
DO - 10.1158/1078-0432.CCR-14-2890
M3 - Article
C2 - 26597303
AN - SCOPUS:84964343747
SN - 1078-0432
VL - 22
SP - 1674
EP - 1686
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -