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
in 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.
Key words
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Acetonitriles
/
Piperazines
/
Pyrimidines
/
Carcinoma, Squamous Cell
/
Lung Neoplasms
Limits:
Animals
/
Humans
Language:
En
Journal:
Cancer Cell
/
Cancer cell
Journal subject:
NEOPLASIAS
Year:
2024
Document type:
Article
Affiliation country:
China
Country of publication:
Estados Unidos