articleCancer CellFeb 22, 2024HYBRID OA

Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer

XTXinyuan TongASAyushi S. PatelEKEejung KimHLHongjun LiYCYueqing Chen

Chinese Academy of Sciences · Center for Excellence in Molecular Cell Science · +20 more institutions

PubMed
Indexed incrossrefpubmed

Abstract

KRASG12C inhibitors (adagrasib and sotorasib) have shown clinical promise in targeting KRASG12C-mutated lung cancers; however, most patients eventually develop resistance. In lung patients with adenocarcinoma with KRASG12C and STK11/LKB1 co-mutations, we find an enrichment of the squamous cell carcinoma gene signature in pre-treatment biopsies correlates with a poor response to adagrasib. Studies of Lkb1-deficient KRASG12C and KrasG12D lung cancer mouse models and organoids treated with KRAS inhibitors reveal tumors invoke a lineage plasticity program, adeno-to-squamous transition (AST), that enables resistance to KRAS inhibition. Transcriptomic and epigenomic analyses reveal ΔNp63 drives AST and modulates…

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108
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22.90
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100%
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Authors

40

Topics & keywords

Topics
Keywords
  • KRAS
  • Cancer research
  • Adenocarcinoma
  • Lung cancer
  • Transcriptome
  • Biology
  • Cancer
  • Gene signature
UN Sustainable Development Goals
  • Good health and well-being
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