Selective targeting of KRAS-driven lung tumorigenesis via unresolved ER stress.

Iwao Shimomura,Koichiro Tatsumi,Tomofumi Yamamoto,Yuji Tada,Minami Kumazaki,Yusuke Yamamoto,Takahiro Ochiya,Naoaki Watanabe

doi:10.1172/jci.insight.137876

Abstract

Lung cancer with oncogenic KRAS makes up a significant proportion of lung cancers and is accompanied by a poor prognosis. Recent advances in understanding the molecular pathogenesis of lung cancer with oncogenic KRAS have enabled the development of drugs, yet mutated KRAS remains undruggable. We performed small-molecule library screening and identified verteporfin, a yes-associated protein 1 (YAP1) inhibitor; verteporfin treatment markedly reduced cell viability in KRAS-mutant lung cancer cells in vitro and suppressed KRAS-driven lung tumorigenesis in vivo. Comparative functional analysis of verteporfin treatment and YAP1 knockdown with siRNA revealed that the cytotoxic effect of verteporfin was at least partially independent of YAP1 inhibition. A whole-transcriptome approach revealed the distinct expression profiles in KRAS-mutant lung cancer cells between verteporfin treatment and YAP1 knockdown and identified the selective involvement of the ER stress pathway in the effects of verteporfin treatment in KRAS-mutant lung cancer, leading to apoptotic cell death. These data provide novel insight to uncover vulnerabilities in KRAS-driven lung tumorigenesis.

Highlights

Lung cancer is the leading cause of cancer death worldwide, and an estimated more than 1 million deaths due to cancer occur per year [1, 2]
We investigated whether yes-associated protein 1 (YAP1) itself is the key determinant of KRAS-driven lung tumorigenesis
There was no significant difference in these gene expression levels, YAP1 expression was generally high in most of the cell lines (Supplemental Figure 1C)

Summary

Introduction

Lung cancer is the leading cause of cancer death worldwide, and an estimated more than 1 million deaths due to cancer occur per year [1, 2]. New advances in the discovery of molecular targeted therapies against oncogenic drivers have brought robust breakthroughs, yet activating mutations of KRAS remain undruggable targets [4, 5]. Major pathways, such as the RAF/MEK/ERK and PI3K/AKT/mTOR networks, are regulated by activated KRAS for the progression of cancer survival. Elevated YAP expression in lung cancer patients has been associated with poor prognosis [9, 14] Despite these recent advances in understanding YAP in the cancer field, the function of YAP in cells or tissues in lung cancer tumorigenesis remains to be explored. Since the reliability of verteporfin as a specific YAP inhibitor remains controversial, further exploration of the mechanism of verteporfin is warranted

Methods

Results

Conclusion