Yun M.RChoi H.MLee Y.WJoo H.SPark C.WChoi J.WKim D.HKang H.NPyo K.-HShin E.JShim H.SSoo R.ACHIH-HSIN YANGLee S.SChang HKim M.HHong M.HKim H.RCho B.C.2020-05-262020-05-2620191757-4676https://www.scopus.com/inward/record.uri?eid=2-s2.0-85074331647&doi=10.15252%2femmm.201910581&partnerID=40&md5=28dc8264431301adecebfe307f204f30https://scholars.lib.ntu.edu.tw/handle/123456789/494880Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALK-rearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. We investigated a novel therapeutic target through screening FDA-approved drugs in ALK-TKI-resistant models. Cerivastatin, the rate-limiting enzyme inhibitor of the mevalonate pathway, showed anti-cancer activity against ALK-TKI resistance in?vitro/in?vivo, accompanied by cytoplasmic retention and subsequent inactivation of transcriptional co-regulator YAP. The marked induction of YAP-targeted oncogenes (EGFR, AXL, CYR61, and TGFβR2) in resistant cells was abolished by cerivastatin. YAP silencing suppressed tumor growth in resistant cells, patient-derived xenografts, and EML4-ALK transgenic mice, whereas YAP overexpression decreased the responsiveness of parental cells to ALK inhibitor. In matched patient samples before/after ALK inhibitor treatment, nuclear accumulation of YAP was mainly detected in post-treatment samples. High expression of YAP in pretreatment samples was correlated with poor response to ALK-TKIs. Our findings highlight a crucial role of YAP in ALK-TKI resistance and provide a rationale for targeting YAP as a potential treatment option for ALK-rearranged patients with acquired resistance to ALK inhibitors. ? 2019 The Authors. Published under the terms of the CC BY 4.0 licenseacquired resistance; ALK; non-small cell lung cancer; statin; YAP[SDGs]SDG3anaplastic lymphoma kinase; atorvastatin; cerivastatin; crizotinib; cysteine rich protein 61; epidermal growth factor receptor; hydroxymethylglutaryl coenzyme A reductase inhibitor; mevalonic acid; transcription factor Yap1; transforming growth factor beta2; verteporfin; anaplastic lymphoma kinase; antineoplastic agent; cell cycle protein; transcription factor; YY1AP1 protein, human; ALK gene; animal cell; animal experiment; animal model; antineoplastic activity; Article; cell viability; clinical article; controlled study; drug screening; female; flow cytometry; gene overexpression; gene rearrangement; gene repression; gene silencing; genetic transfection; high throughput screening; human; human cell; human tissue; immunoblotting; immunofluorescence; immunohistochemistry; in vitro study; in vivo study; male; mouse; mutagenesis; non small cell lung cancer; nonhuman; oncogene; priority journal; protein expression; protein function; protein targeting; Sanger sequencing; signal transduction; tumor biopsy; tumor growth; upregulation; animal; drug resistance; gene expression regulation; genetics; lung tumor; metabolism; non small cell lung cancer; nude mouse; tumor cell line; Anaplastic Lymphoma Kinase; Animals; Antineoplastic Agents; Carcinoma, Non-Small-Cell Lung; Cell Cycle Proteins; Cell Line, Tumor; Drug Resistance, Neoplasm; Female; Gene Expression Regulation, Neoplastic; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Lung Neoplasms; Mice; Mice, Nude; Transcription Factorsjournal article10.15252/emmm.201910581316333042-s2.0-85074331647