title: Functional genomics screen identifies YAP1 as a key determinant to enhance treatment sensitivity in lung cancer cells.
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.
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Haiying
authors.initials: H
authors.lastname: Cheng
authors.affiliation: Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Center of Medical Imaging and Image-Guided Therapy, Guangzhou, China.
authors.forename: Zhenfeng
authors.initials: Z
authors.lastname: Zhang
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Rodriguez-Barrueco
authors.affiliation: Department of Pathology, Weill Cornell University Medical Center, New York, NY, USA.
authors.forename: Alain
authors.initials: A
authors.lastname: Borczuk
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Huijie
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Biomedical Informatics, Columbia University, New York, NY, USA.|Department of Precision Medicine, Oncology Research Unit, Pfizer Inc., Pearl River, NY, USA.
authors.forename: Jiyang
authors.initials: J
authors.lastname: Yu
authors.affiliation: Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Silva
authors.affiliation: Department of Radiation Oncology, Columbia University College of Physicians and Surgeons, New York, NY, USA.
authors.forename: Simon K
authors.initials: SK
authors.lastname: Cheng
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, NY, USA.
authors.forename: Roman
authors.initials: R
authors.lastname: Perez-Soler
authors.affiliation: Department of Oncology, Albert Einstein College of Medicine of Yeshiva University/Montefiore Medical Center, Bronx, NY, USA.|Division of Hematology/Oncology, Herbert Irving Comprehensive Cancer Center, New York Presbyterian Hospital-Columbia University Medical Center, New York, NY, USA.
authors.forename: Balazs
authors.initials: B
authors.lastname: Halmos
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics*; D000970:Antineoplastic Agents / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000473:pathology*; D010750:Phosphoproteins / Q000235:genetics*; D011836:Radiation Tolerance / Q000235:genetics*; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D010750:Phosphoproteins; D014157:Transcription Factors; D000091102:YAP-Signaling Proteins; C088374:YAP1 protein, human
keywords: RNAi screen; YAP1; lung cancer; platinum resistance; radiation