Adeno-to-Squamous Transition Leads to Resistance to KRAS Inhibitor in Lung Cancer
KRASG12C inhibitors,including Adagrasib and Sotorasib,have shown clinical efficacy in target-ing KRASG12C-mutated lung cancers.However,most patients develop resistance to these therapies,and it is impor-tant to explore the mechanism of KRAS inhibitor resistance.STK11(serine/threonine kinase 11)/LKB1 is frequently co-mutated with KRAS in non-small cell lung cancer.Loss of tumor suppressor gene LKB1 decreases sensitivity to drug treatment.In KRAS/LKB1 mutant lung adenocarcinoma(ADC)patients treated with Adagrasib monotherapy(KRYSTAL-1),enrichment for a squamous gene signature in the pre-treatment biopsy is significantly correlated with shorter treatment duration.Furthermore,integrative analysis of KCL(KRASLSL-G12C/+;Lkb1flox/flox)mouse model and KDL(KrasLSL-G12D/+;Lkb1flox/flox)organoid model of lung cancer demonstrates that AST(adeno-to-squamous tran-sition)is a prominent mechanism of acquired resistance to KRAS inhibition.The transcriptomic and epigenomic analyses further reveal that Elf5-ANp63 axis regulates AST and modulates response to KRAS inhibition.Important-ly,high expression of KRT6A in high-plasticity cell state during AST is associated with poor Adagrasib response.Taken together,the study demonstrates that AST is one of the mechanisms of KRAS inhibitor resistance and pro-vides potential biomarkers for KRAS-targeted therapies in lung cancer.
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