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Title: Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells
Author: Cheng, Haiying
Zhang, Zhenfeng
Rodriguez Barrueco, Ruth
Borczuk, Alain
Liu, Huijie
Yu, Jiyang
Silva, Jose M.
Cheng, Simon K.
Perez-Soler, Roman
Halmos, Balazs
Keywords: Proteïnes
Issue Date: 17-May-2016
Publisher: Impact Journals
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: Oncotarget, 2016, vol. 7, num. 20, p. 28976-28988
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ISSN: 1949-2553
Appears in Collections:Articles publicats en revistes (Patologia i Terapèutica Experimental)

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