ArticleThe Journal of clinical investigation2025
KRAS mutants confer platinum resistance by regulating ALKBH5 posttranslational modifications in lung cancer.
Article in The Journal of clinical investigation, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed.
- SMARCA4 deficiency contributes to platinum resistance in non-small cell lung cancer by activating the NF-κB-BIRC2/BIRC3 signaling axis.Journal of thoracic disease · 2026Article
- Hypoxia-inducible factors: Regulatory functions and status as a therapeutic target in gastric cancer (Review).Oncology letters · 2026Review
- The Role of NMedComm · 2026Review
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- Posttranslational modifications in regulating Notch signaling pathway and tumor angiogenesis: from molecular mechanisms to therapeutic applications.Journal of molecular cell biology · 2026Review
- KRAS and MYC synergistic inhibition: a powerful strategy targeting KRAS-mutant cancers.Molecular cancer · 2026Review
- Multi-omics integration in deciphering non-small cell lung cancer drug resistance: current status, challenges, and future prospects.Hereditas · 2026Review
- Regulation of Translation of ATF4 mRNA: A Focus on Translation Initiation Factors and RNA-Binding Proteins.Cells · 2026Review
- Targeting shared mechanisms of cisplatin resistance and metastasis in lung cancer for novel therapeutic strategies.Discover oncology · 2026Review
- Serum Metabolomic Profiles Predict Sensitivity and Toxicity to Platinum- Fluorouracil Chemotherapy in a Gastric Cancer Xenograft Model.Combinatorial chemistry & high throughput screening · 2026Article
- Context-dependent functions of ALKBH5: a mechanistic framework linking cellular stress responses, immune regulation, viral infection, and therapeutic vulnerabilities.Frontiers in immunology · 2026Review
- Association of NDRG4 gene methylation in peripheral blood leukocytes with gastric cancer risk, chemotherapy efficacy and prognosis.Frontiers in oncology · 2026Article
- Targeting the METTL3/PCNA axis with STM2457 overcomes cisplatin resistance in osteosarcoma.Translational cancer research · 2025Article
- Regulation of cisplatin resistance in lung cancer by epigenetic mechanisms.Clinical epigenetics · 2025Review
- Mechanistic insights into the role of RNA demethylase ALKBH5 in malignant tumor therapy.Journal of translational medicine · 2025Review
- Quantifying the mRNA epitranscriptome reveals epitranscriptome signatures and roles in cancer.Cellular and molecular life sciences : CMLS · 2025Article
- Dissecting the METTL3/STC2 axis in colorectal cancer: implications for drug resistance and metastasis.Cell biology and toxicology · 2025Article
- M6A RNA modification: focusing on non-small cell lung cancer progression, therapeutic strategies and challenges.Frontiers in oncology · 2025Review
- Disrupting DDB2-DNA Interaction by Lapatinib Enhances Chemotherapy Sensitivity.International journal of biological sciences · 2025Article
- METTL3-mediated m6A methylation on lncRNA H19 inhibits intrahepatic cholangiocarcinoma progression through PPARγ downregulation.International journal of biological sciences · 2025Article
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Authors and funding
11 authors.
Funding
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.
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