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

Mi Ran Yun,Chae Won Park,Hye Ryun Kim,Hyeong Seok Joo,Min Hee Hong,Kyoung‐Ho Pyo,Dong Hwi Kim,Hyo Sup Shim,James Chih‐Hsin Yang,Sung Sook Lee,Hun Mi Choi,Jae Woo Choi,Ross A Soo,Han Na Kang,Min Hwan Kim,Byoung Chul Cho,Hyun Chang,Eun Joo Shin,You Won Lee

doi:10.15252/emmm.201910581

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.

Highlights

Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALKrearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood
Considering that cerivastatin was withdrawn from the market in 2001 due to fatal rhabdomyolysis and kidney failure (Furberg & Pitt, 2001), we evaluated the anti-proliferative capability of the other clinically available statins, atorvastatin and simvastatin, in CR cells
They were used at higher concentrations than cerivastatin, these statins successfully inhibited cell growth at the concentration range reported in other previous preclinical studies (Fig EV1A and Appendix Fig S2A)

Summary

Introduction

Clinical benefit of ALK tyrosine kinase inhibitors (ALK-TKIs) in ALKrearranged lung cancer has been limited by the inevitable development of acquired resistance, and bypass-molecular resistance mechanisms remain poorly understood. 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. 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. 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

Objectives

Methods

Results

Conclusion