Adeno-to-Squamous Transition Leads to Resistance to KRAS Inhibitor in Lung Cancer
TONG Xinyuan, XUE Yun, ZHANG Ningxia, JI Hongbin*
KRASG12C inhibitors, including Adagrasib and Sotorasib, have shown clinical efficacy in targeting KRASG12C-mutated lung cancers. However, most patients develop resistance to these therapies, and it is important 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 transition) is a prominent mechanism of acquired resistance to KRAS inhibition. The transcriptomic and epigenomic analyses further reveal that Elf5-ΔNp63 axis regulates AST and modulates response to KRAS inhibition. Importantly, 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 provides potential biomarkers for KRAS-targeted therapies in lung cancer.
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