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Comment
. 2024 Aug 26;16(3):mjae013.
doi: 10.1093/jmcb/mjae013.

Comments on 'Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer'

Xinyuan Tong  1 , Ningxia Zhang  2 , Yun Xue  1   3 , Hongbin Ji  1   3   4
Affiliations
Comment

Comments on 'Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer'

Xinyuan Tong et al. J Mol Cell Biol. .
No abstract available

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Figures

Figure 1
Figure 1
Current understanding of the molecular mechanisms underlying the AST process. (i) LKB1 acts as a tumor suppressor; its inactivation leads to dysregulation of the mTOR and LOX pathways and consequently initiates the malignant progression of KrasG12D-mutant lung ADC. (ii) LKB1 also acts as an epigenetic and metabolic regulator; its inactivation leads to deregulation of PPP and impairment of the AMPK–ACC–FAO axis, resulting in excessive ROS accumulation. The uncontrolled ROS accumulation suppresses FOXO3A-mediated WNT signaling, disrupts the homeostasis within the ADC- and SCC-specific TF network, and promotes AST. (iii) Through an unknown mechanism, excessive ROS accumulation reverses the activated HIF1α–LOX signaling, which is induced by LKB1 inactivation, resulting in collagen depletion and subsequent phosphorylation of YAP. Inactivation of YAP can relieve ZEB2-mediated repression of ΔNp63. The counteracting lineage-specific TF network, including ADC-related TFs (NKX2-1 and FOXA2) and SCC-related TFs (ΔNp63 and SOX2), finely tunes the AST process. ELF5 acts as an upstream positive regulator of NKX2-1 and inhibits VEZF1-mediated upregulation of ΔNp63. Thus, ELF5 is a predictive biomarker of sensitivity to KRAS inhibitors, while ΔNp63/KRT6A predicts a poor response to KRAS inhibitors. (iv) Epigenetic regulators, such as EZH2 and LSD1, also play important roles in maintaining the identities of ADC and SCC, respectively. mTOR, mammalian target of rapamycin; LOX, lysyl oxidase; PPP, pentose phosphate pathway; ACC, acetyl-CoA carboxylase; HIF1α, hypoxia-inducible factor 1α; YAP, Yes-associated protein; ZEB2, zinc finger E-box-binding homeobox 2; VEZF1, vascular endothelial zinc finger 1; EZH2, enhancer of zeste homolog 2; LSD1, lysine-specific histone demethylase 1.
See this image and copyright information in PMC

Comment on

  • Adeno-to-squamous transition drives resistance to KRAS inhibition in LKB1 mutant lung cancer.
    Tong X, Patel AS, Kim E, Li H, Chen Y, Li S, Liu S, Dilly J, Kapner KS, Zhang N, Xue Y, Hover L, Mukhopadhyay S, Sherman F, Myndzar K, Sahu P, Gao Y, Li F, Li F, Fang Z, Jin Y, Gao J, Shi M, Sinha S, Chen L, Chen Y, Kheoh T, Yang W, Yanai I, Moreira AL, Velcheti V, Neel BG, Hu L, Christensen JG, Olson P, Gao D, Zhang MQ, Aguirre AJ, Wong KK, Ji H. Tong X, et al. Cancer Cell. 2024 Mar 11;42(3):413-428.e7. doi: 10.1016/j.ccell.2024.01.012. Epub 2024 Feb 22. Cancer Cell. 2024. PMID: 38402609

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