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KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer
Fang Yu, … , Tongjun Gu, Zhijian Qian
Fang Yu, … , Tongjun Gu, Zhijian Qian
Published February 17, 2025
Citation Information: J Clin Invest. 2025;135(6):e185149. https://doi.org/10.1172/JCI185149.
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Research Article Cell biology Oncology Article has an altmetric score of 8

KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer

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Abstract

Constitutively active mutations of KRAS are prevalent in non–small cell lung cancer (NSCLC). However, the relationship between these mutations and resistance to platinum-based chemotherapy and the underlying mechanisms remain elusive. In this study, we demonstrate that KRAS mutants confer resistance to platinum in NSCLC. Mechanistically, KRAS mutants mediate platinum resistance in NSCLC cells by activating ERK/JNK signaling, which inhibits AlkB homolog 5 (ALKBH5) N6-methyladenosine (m6A) demethylase activity by regulating posttranslational modifications (PTMs) of ALKBH5. Consequently, the KRAS mutant leads to a global increase in m6A methylation of mRNAs, particularly damage-specific DNA-binding protein 2 (DDB2) and XPC, which are essential for nucleotide excision repair. This methylation stabilized the mRNA of these 2 genes, thus enhancing NSCLC cells’ capability to repair platinum-induced DNA damage and avoid apoptosis, thereby contributing to drug resistance. Furthermore, blocking KRAS-mutant–induced m6A methylation, either by overexpressing a SUMOylation-deficient mutant of ALKBH5 or by inhibiting methyltransferase-like 3 (METTL3) pharmacologically, significantly sensitizes KRAS-mutant NSCLC cells to platinum drugs in vitro and in vivo. Collectively, our study uncovers a mechanism that mediates KRAS-mutant–induced chemoresistance in NSCLC cells by activating DNA repair through the modulation of the ERK/JNK/ALKBH5 PTM-induced m6A modification in DNA damage repair–related genes.

Authors

Fang Yu, Shikan Zheng, Chunjie Yu, Sanhui Gao, Zuqi Shen, Rukiye Nar, Zhexin Liu, Shuang Huang, Lizi Wu, Tongjun Gu, Zhijian Qian

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Figure 1

KRAS constitutively active mutation confers NSCLC platinum resistance.

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KRAS constitutively active mutation confers NSCLC platinum resistance.
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(A) Western blot analysis showing protein levels as indicated in BEAS-2B cells. (B) Western blot analysis showing the protein levels as indicated in KRAS WT or -mutant NSCLC cells with or without cisplatin treatment. (C) Comet analysis for KRAS WT and mutant NSCLC cells with or without cisplatin treatment. (D) Cell apoptosis analyses for KRAS WT or -mutant NSCLC cells with or without cisplatin treatment. (E) Colony-forming analyses for KRAS WT or mutant NSCLC cells with or without cisplatin treatment. (F) Annexin V staining analysis showing that overexpression of the KRAS-mutant significantly inhibits cisplatin-induced cell apoptosis in NCI-H522 cells. (G) Western blot analysis showing that overexpression of the KRAS-mutant significantly inhibits cisplatin-induced DNA damage in NCI-H522 cells. (H) Annexin V staining analysis showing that KRAS KD significantly facilitates cisplatin-induced cell apoptosis in NCI-H23 cells. (I) Western blot analysis showing that KRAS KD significantly promotes cisplatin-induced DNA damage in NCI-H23 cells. (J–M) CCK8 analyses showing the effect of cisplatin and PTX treatment on the cell proliferation of KRAS WT and -mutant NSCLC cells. (N and O) CCK8 analysis indicating the effect of KRAS KD on PTX sensitivity of KRAS-mutant cells. In C–F, H, and J–O, data are presented as mean ± SD, with ordinary 1-way ANOVA with Dunnett’s multiple-comparison test used for C, D, F, H, and J–O and 2-tailed Student’s t test for E. *P < 0.05; **P < 0.01; ***P < 0.001; ****P < 0.0001.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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