KRAS is one of the most frequently mutated genes in non-small cell lung cancer. Recent development of KRAS inhibitors has revolutionized the treatment of KRAS-mutant lung cancer. Cancer cell plasticity, especially the adeno-to-squamous transition (AST), has been proposed to contribute to drug resistance, e.g., EGFR tyrosine kinase inhibitor resistance. Andrew J. Aguirre et al showed that two out of nine lung adenocarcinoma (ADC) patients relapsed after KRASG12C inhibitor adagrasib treatments showed squamous transition upon re-biopsy. However, the link between AST and KRAS inhibitor resistance as well as the evolutionary path of such phenotypic transition still remain largely unknown.
In a study published in Cancer Cell, researchers led by Prof. JI Hongbin from the Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences, together with Prof. Kwok-Kin Wong from New York University Langone Health, Prof. Andrew J. Aguirre from Dana-Farber Cancer Institute and Prof. Michael Q. Zhang from Tsinghua University reported that adeno-to-squamous transition (AST) drives the resistance to KRAS inhibition in LKB1-mutant lung cancer, and KRT6A is a predicative biomarker of poor KRAS inhibitor response.
In this study, through analyses of 116 lung cancer patients enrolled in KRYSTAL-1 trial, a phase I/II study of adagrasib in KRASG12C mutated lung cancers, the researchers identified 68 patients who had available transcriptomic data on pre-treatment biopsy samples. The data showed that a high squamous signature at baseline was significantly correlated with poor clinical responses to KRASG12C inhibitor. Interestingly, this correlation is specifically observed in STK11/LKB1-mutant patients, but not in STK11/LKB1-wildtype patients.
They further established two pre-clinical mouse models including KRASLSL-G12C/+;Lkb1flox/flox (KCL) and KRASLSL-G12C/+;Trp53flox/flox (KCP) for adagrasib treatment, and demonstrate that only in Lkb1 deficient mouse model the squamous transition drives KRAS inhibitor resistance. Using two organoids models derived from KCL and KrasLSL-G21D/+;Lkb1flox/flox (KDL) mouse models, the researchers further proved that the KRAS inhibitor resistance is associated with squamous transition. They found that KRAS signaling was downregulated, and the squamous-related signature was increased in drug-resistant mouse tumors and organoids, indicative of a KRAS signaling-independent state of squamous transitioned lung cancer. Using the reporter mouse visualizing ΔNp63 expression coupled with multi-omic data, they detected the dynamical progression of squamous transition and identified the Elf5-ΔNp63 axis regulated squamous transition and drug response to KRAS inhibitors.
Moreover, they also identified an intermediate stage during AST with increased high-plasticity cell state (HPCS) signature, which showed the co-expression of alveolar and basal cell feature. To identify potential biomarkers predicting squamous transition and adagrasib resistance, the researchers analyzed the commonly enriched genes in HPCS clusters and adagrasib-resistant tumors and identified an AST plasticity signature (6 overlapping genes including Krt6a). The high expression of AST plasticity signature and KRT6A was significantly correlated with poor clinical responses to KRASG12C inhibitor.
In summary, these research findings improve the understanding of the AST and the KRAS inhibitor resistance, while nominating important biomarker relationships for future clinical study.
Contact: hbji@sibcb.ac.cn
Reference: https://doi.org/10.1016/j.ccell.2024.01.012
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