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 language | English |
|---|---|
| Article number | e10581 |
| Journal | EMBO Molecular Medicine |
| Volume | 11 |
| Issue number | 12 |
| DOIs | |
| Publication status | Published - 2019 Dec 1 |
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All Science Journal Classification (ASJC) codes
- Molecular Medicine
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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 journal › Article
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.
UR - http://www.scopus.com/inward/record.url?scp=85074331647&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074331647&partnerID=8YFLogxK
U2 - 10.15252/emmm.201910581
DO - 10.15252/emmm.201910581
M3 - Article
C2 - 31633304
AN - SCOPUS:85074331647
VL - 11
JO - EMBO Molecular Medicine
JF - EMBO Molecular Medicine
SN - 1757-4676
IS - 12
M1 - e10581
ER -