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

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2 Citations (Scopus)

Abstract

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.

Original languageEnglish
Article numbere10581
JournalEMBO Molecular Medicine
Volume11
Issue number12
DOIs
Publication statusPublished - 2019 Dec 1

All Science Journal Classification (ASJC) codes

  • Molecular Medicine

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    Yun, M. R., Choi, H. M., Lee, Y. W., Joo, H. S., Park, C. W., Choi, J. W., Kim, D. H., Kang, H. N., Pyo, K. H., Shin, E. J., Shim, H. S., Soo, R. A., Yang, J. C. H., Lee, S. S., Chang, H., Kim, M. H., Hong, M. H., Kim, H. R., & Cho, B. C. (2019). Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer. EMBO Molecular Medicine, 11(12), [e10581]. https://doi.org/10.15252/emmm.201910581