Adeno‑to‑Squamous Transition Drives Resistance to KRAS Inhibition in LKB1 Mutant Lung Cancer

Rákkutatás · NSCLC · KRAS

In KRASG12C‑mutated lung adenocarcinoma with STK11/LKB1 co‑mutations, an adeno‑to‑squamous transition (AST) lineage‑plasticity program underlies resistance to KRAS inhibitors, and elevated AST‑plasticity or KRT6A expression in pretreatment tumors predicts poor response to adagrasib.

KRASG12C inhibitors such as adagrasib and sotorasib have shown activity in KRASG12C‑mutated non‑small‑cell lung cancer, yet most patients eventually develop resistance. In patients with adenocarcinoma carrying both KRASG12C and STK11/LKB1 mutations, we found an enrichment of squamous cell signature in pretreatment biopsies, correlating with poor adagrasib response. Using Lkb1‑deficient KRASG12C and KrasG12D mouse models and organoids treated with KRAS inhibitors, we uncovered a lineage‑plasticity program—adenocarcinoma‑to‑squamous (AST)—that drives resistance. Transcriptomic and epigenomic analyses identified ΔNp63 as a key driver of AST and revealed an intermediate high‑plastic state marked by an AST plasticity signature and KRT6A expression. Baseline expression of the AST signature and KRT6A correlated with diminished therapeutic response. These results highlight AST-mediated plasticity as a mechanism of resistance and identify baseline biomarkers for predicting patient response to KRAS‑targeted therapies.

Identifying AST as a driver of KRAS‑inhibitor resistance provides a mechanistic explanation for clinical failures in KRASG12C‑mutated NSCLC and reveals measurable biomarkers (AST plasticity signature, KRT6A) that could guide therapeutic selection and inform combination strategies to prevent or overcome resistance.

Bizonyítékszint: Korai humán adat. Kis vagy feltáró emberi adat.

Eredeti forrás

Kapcsolódó jelek