Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.
Cancer Cell
; 42(3): 413-428.e7, 2024 Mar 11.
Article
em En
| MEDLINE
| ID: mdl-38402609
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 response to KRAS inhibition. We identify an intermediate high-plastic cell state marked by expression of an AST plasticity signature and Krt6a. Notably, expression of the AST plasticity signature and KRT6A at baseline correlates with poor adagrasib responses. These data indicate the role of AST in KRAS inhibitor resistance and provide predictive biomarkers for KRAS-targeted therapies in lung cancer.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Acetonitrilas
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Piperazinas
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Pirimidinas
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Carcinoma de Células Escamosas
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Neoplasias Pulmonares
Limite:
Animals
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Humans
Idioma:
En
Revista:
Cancer Cell
Ano de publicação:
2024
Tipo de documento:
Article