Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells

Haiying Cheng, Zhenfeng Zhang, R. Ruth Rodriguez-Barrueco, Alain Borczuk, Huijie Liu, Jiyang Yu, Jose M. Silva, Simon K. Cheng, Roman Perez-Soler, Balazs Halmos

Research output: Contribution to journalArticle

26 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)28976-28988
Number of pages13
JournalOncotarget
Volume7
Issue number20
DOIs
StatePublished - May 17 2016

Fingerprint

Genomics
Non-Small Cell Lung Carcinoma
Lung Neoplasms
Cisplatin
Platinum
Radiation
Therapeutics
RNA Interference
Ionizing Radiation
Oncogenes
Radiotherapy
Down-Regulation
Pharmacology
Staining and Labeling
Survival
DNA
Genes
Proteins
Erlotinib Hydrochloride

Keywords

  • Lung cancer
  • Platinum resistance
  • Radiation
  • RNAi screen
  • YAP1

ASJC Scopus subject areas

  • Oncology

Cite this

Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells. / Cheng, Haiying; Zhang, Zhenfeng; Rodriguez-Barrueco, R. Ruth; Borczuk, Alain; Liu, Huijie; Yu, Jiyang; Silva, Jose M.; Cheng, Simon K.; Perez-Soler, Roman; Halmos, Balazs.

In: Oncotarget, Vol. 7, No. 20, 17.05.2016, p. 28976-28988.

Research output: Contribution to journalArticle

Cheng, Haiying ; Zhang, Zhenfeng ; Rodriguez-Barrueco, R. Ruth ; Borczuk, Alain ; Liu, Huijie ; Yu, Jiyang ; Silva, Jose M. ; Cheng, Simon K. ; Perez-Soler, Roman ; Halmos, Balazs. / Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells. In: Oncotarget. 2016 ; Vol. 7, No. 20. pp. 28976-28988.
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