4.7 Article

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

Journal

JCI INSIGHT
Volume 6, Issue 7, Pages -

Publisher

AMER SOC CLINICAL INVESTIGATION INC
DOI: 10.1172/jci.insight.137876

Keywords

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Funding

  1. Project for Cancer Research and Therapeutic Evolution (P-CREATE) [17cm0106402h0002]
  2. MEXT KAKENHI [17H04991]
  3. Naito Foundation
  4. Yokoyama Foundation for Clinical Pharmacology
  5. Kobayashi Foundation
  6. Foundation for Promotion of Cancer Research in Japan
  7. Grants-in-Aid for Scientific Research [17H04991] Funding Source: KAKEN

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The study found that verteporfin can effectively inhibit the viability of KRAS-mutant lung cancer cells and suppress KRAS-driven lung tumors. The mechanism of verteporfin action is partially independent of YAP1 inhibition and leads to apoptotic cell death in KRAS-mutant lung cancer cells by inducing endoplasmic reticulum stress pathway.
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.

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