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

Research output: Contribution to journalArticle

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

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Protein-Tyrosine Kinases
Lung Neoplasms
Mevalonic Acid
Enzyme Inhibitors
Therapeutics
Oncogenes
Heterografts
Transgenic Mice
Neoplasms
Growth
Pharmaceutical Preparations
cerivastatin

All Science Journal Classification (ASJC) codes

  • Molecular Medicine

Cite this

Yun, Mi Ran ; Choi, Hun Mi ; Lee, You Won ; Joo, Hyeong Seok ; Park, Chae Won ; Choi, Jae Woo ; Kim, Dong Hwi ; Kang, Han Na ; Pyo, Kyoung Ho ; Shin, Eun Joo ; Shim, Hyo Sup ; Soo, Ross A. ; Yang, James Chih Hsin ; Lee, Sung Sook ; Chang, Hyun ; Kim, Min Hwan ; Hong, Min Hee ; Kim, Hye Ryun ; Cho, Byoung Chul. / Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer. In: EMBO Molecular Medicine. 2019 ; Vol. 11, No. 12.
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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.",
author = "Yun, {Mi Ran} and Choi, {Hun Mi} and Lee, {You Won} and Joo, {Hyeong Seok} and Park, {Chae Won} and Choi, {Jae Woo} and Kim, {Dong Hwi} and Kang, {Han Na} and Pyo, {Kyoung Ho} and Shin, {Eun Joo} and Shim, {Hyo Sup} and Soo, {Ross A.} and Yang, {James Chih Hsin} and Lee, {Sung Sook} and Hyun Chang and Kim, {Min Hwan} and Hong, {Min Hee} and Kim, {Hye Ryun} and Cho, {Byoung Chul}",
year = "2019",
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Yun, MR, Choi, HM, Lee, YW, Joo, HS, Park, CW, Choi, JW, Kim, DH, Kang, HN, Pyo, KH, Shin, EJ, Shim, HS, Soo, RA, Yang, JCH, Lee, SS, Chang, H, Kim, MH, Hong, MH, Kim, HR & Cho, BC 2019, 'Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer', EMBO Molecular Medicine, vol. 11, no. 12, e10581. https://doi.org/10.15252/emmm.201910581

Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer. / Yun, Mi Ran; Choi, Hun Mi; Lee, You Won; Joo, Hyeong Seok; Park, Chae Won; Choi, Jae Woo; Kim, Dong Hwi; Kang, Han Na; Pyo, Kyoung Ho; Shin, Eun Joo; Shim, Hyo Sup; Soo, Ross A.; Yang, James Chih Hsin; Lee, Sung Sook; Chang, Hyun; Kim, Min Hwan; Hong, Min Hee; Kim, Hye Ryun; Cho, Byoung Chul.

In: EMBO Molecular Medicine, Vol. 11, No. 12, e10581, 01.12.2019.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Targeting YAP to overcome acquired resistance to ALK inhibitors in ALK-rearranged lung cancer

AU - Yun, Mi Ran

AU - Choi, Hun Mi

AU - Lee, You Won

AU - Joo, Hyeong Seok

AU - Park, Chae Won

AU - Choi, Jae Woo

AU - Kim, Dong Hwi

AU - Kang, Han Na

AU - Pyo, Kyoung Ho

AU - Shin, Eun Joo

AU - Shim, Hyo Sup

AU - Soo, Ross A.

AU - Yang, James Chih Hsin

AU - Lee, Sung Sook

AU - Chang, Hyun

AU - Kim, Min Hwan

AU - Hong, Min Hee

AU - Kim, Hye Ryun

AU - Cho, Byoung Chul

PY - 2019/12/1

Y1 - 2019/12/1

N2 - 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.

AB - 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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