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Lookup NU author(s): Dr Ruth Rodriguez Barrueco
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
Survival for lung cancer patients remains dismal and is largely attributed to treatment resistance. To identify novel target genes the modulation of which could modify platinum resistance, we performed a high-throughput RNAi screen and identified Yes-associated protein (YAP1), a transcription coactivator and a known oncogene, as a potential actionable candidate. YAP1 ablation significantly improved sensitivities not only to cisplatin but also to ionizing radiation, both of which are DNA-damaging interventions, in non-small cell lung cancer (NSCLC) cells. Overall YAP1 was expressed in 75% of NSCLC specimens, whereas nuclear YAP1 which is the active form was present in 45% of 124 resected NSCLC. Interestingly, EGFR-mutated or KRAS-mutated NSCLC were associated with higher nuclear YAP1 staining in comparison to EGFR/KRAS wild-type. Relevantly, YAP1 downregulation improved sensitivity to erlotinib, an EGFR inhibitor. A pharmacological inhibitor of YAP1 signaling, verteporfin also synergized with cisplatin, radiation and erlotinib in NSCLC cells by potentiating cisplatin and radiation-related double-stranded breaks and decreasing expression of YAP1 and EGFR. Taken together, our study is the first to indicate the potential role of YAP1 as a common modulator of resistance mechanisms and a potential novel, actionable target that can improve responses to platinum, radiation and EGFR-targeted therapy in lung cancer.
Author(s): Cheng H, Zhang Z, Rodriguez-Barrueco R, Borczuk A, Liu H, Yu J, Silva JM, Cheng SK, Perez-Soler R, Halmos B
Publication type: Article
Publication status: Published
Journal: Oncotarget
Year: 2016
Volume: 7
Issue: 20
Pages: 28976-28988
Print publication date: 17/05/2016
Online publication date: 22/12/2015
Acceptance date: 21/11/2015
Date deposited: 19/08/2016
ISSN (electronic): 1949-2553
Publisher: Impact Journals LLC
URL: http://dx.doi.org/10.18632/oncotarget.6721
DOI: 10.18632/oncotarget.6721
PubMed id: 26716514
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