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Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer

 Mi Ran Yun  ;  Hun Mi Choi  ;  You Won Lee  ;  Hyeong Seok Joo  ;  Chae Won Park  ;  Jae Woo Choi  ;  Dong Hwi Kim  ;  Han Na Kang  ;  Kyoung‐Ho Pyo  ;  Eun Joo Shin  ;  Hyo Sup Shim  ;  Ross A Soo  ;  James Chih‐Hsin Yang  ;  Sung Sook Lee  ;  Hyun Chang  ;  Min Hwan Kim  ;  Min Hee Hong  ;  Hye Ryun Kim  ;  Byoung Chul Cho 
 EMBO MOLECULAR MEDICINE, Vol.11(12) : e10581, 2019 
Journal Title
Issue Date
ALK ; YAP ; acquired resistance ; non-small cell lung cancer ; statin
Clinical 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.
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Appears in Collections:
1. College of Medicine (의과대학) > Dept. of Internal Medicine (내과학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > BioMedical Science Institute (의생명과학부) > 1. Journal Papers
1. College of Medicine (의과대학) > Dept. of Pathology (병리학교실) > 1. Journal Papers
1. College of Medicine (의과대학) > Yonsei Biomedical Research Center (연세의생명연구원) > 1. Journal Papers
Yonsei Authors
Kim, Min Hwan(김민환) ORCID logo https://orcid.org/0000-0002-1595-6342
Kim, Hye Ryun(김혜련) ORCID logo https://orcid.org/0000-0002-1842-9070
Park, Chae Won(박채원)
Shim, Hyo Sup(심효섭) ORCID logo https://orcid.org/0000-0002-5718-3624
Yun, Mi Ran(윤미란)
Cho, Byoung Chul(조병철) ORCID logo https://orcid.org/0000-0002-5562-270X
Pyo, Kyoung Ho(표경호) ORCID logo https://orcid.org/0000-0001-5428-0288
Hong, Min Hee(홍민희) ORCID logo https://orcid.org/0000-0003-3490-2195
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