Selective targeting of KRAS-driven lung tumorigenesis via unresolved ER stress
Iwao Shimomura, Naoaki Watanabe, Tomofumi Yamamoto, Minami Kumazaki, Yuji Tada, Koichiro Tatsumi, Takahiro Ochiya, Yusuke Yamamoto
Iwao Shimomura, Naoaki Watanabe, Tomofumi Yamamoto, Minami Kumazaki, Yuji Tada, Koichiro Tatsumi, Takahiro Ochiya, Yusuke Yamamoto
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Research Article Cell biology Oncology

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

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.

Authors

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

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Figure 5

Verteporfin treatment is associated with the ER stress pathway.

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Verteporfin treatment is associated with the ER stress pathway. (A) Venn...
(A) Venn diagram showing upregulated genes and downregulated genes following treatment with YAP1 siRNAs and verteporfin at various concentrations. (B) Correlation of the normalized enrichment scores following verteporfin treatment and YAP1 knockdown from GSEA of all hallmark gene sets. (C) Related pathways and functional annotation of genes specifically altered by verteporfin treatment analyzed by ingenuity pathway analysis (QIAGEN). (D) GSEA to assess apoptotic signaling in response to ER stress in A-549 cells treated with various concentrations of verteporfin. GO, Gene Ontology. The P values in the graphs were calculated by GSEA. (E) Heatmap of leading-edge genes in the ER stress pathway.