Academic Journal
The PKMYT1-ALDOA axis drives chemoresistance in cholangiocarcinoma by enhancing glycolysis and MRE11 lactylation.
| Τίτλος: | The PKMYT1-ALDOA axis drives chemoresistance in cholangiocarcinoma by enhancing glycolysis and MRE11 lactylation. |
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| Συγγραφείς: | Wu W; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Wang J; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Yang W; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066CX, The Netherlands., Sun Z; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Sun X; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Wang Y; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Lian S; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Zheng J; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Zhou Y; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Shen W; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Hu P; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Guo J; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Wu Q; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Wang S; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066CX, The Netherlands., Jia Q; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Yuan S; Department of Hepatobiliary Surgery, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University (Naval Medical University), Shanghai 200438, China., Bernards R; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066CX, The Netherlands., Qin W; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China., Jin H; State Key Laboratory of Systems Medicine for Cancer, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200032, China.; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam 1066CX, The Netherlands. |
| Πηγή: | Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2026 Oct 06; Vol. 123 (40), pp. e2623500123. Date of Electronic Publication: 2026 Sep 29. |
| Τύπος έκδοσης: | Journal Article |
| Γλώσσα: | English |
| Στοιχεία περιοδικού: | Publisher: National Academy of Sciences Country of Publication: United States NLM ID: 7505876 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1091-6490 (Electronic) Linking ISSN: 00278424 NLM ISO Abbreviation: Proc Natl Acad Sci U S A Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : National Academy of Sciences |
| Ιατρικοί όροι (MeSH): | Cholangiocarcinoma*/metabolism , Cholangiocarcinoma*/drug therapy , Cholangiocarcinoma*/pathology , Cholangiocarcinoma*/genetics , Drug Resistance, Neoplasm*/drug effects , Glycolysis*/drug effects , Bile Duct Neoplasms*/metabolism , Bile Duct Neoplasms*/drug therapy , Bile Duct Neoplasms*/pathology , Bile Duct Neoplasms*/genetics , MRE11 Homologue Protein*/metabolism , MRE11 Homologue Protein*/genetics , Membrane Proteins*/metabolism , Membrane Proteins*/genetics , Fructose-Bisphosphate Aldolase*/metabolism , Fructose-Bisphosphate Aldolase*/genetics , Protein Serine-Threonine Kinases*/metabolism , Protein Serine-Threonine Kinases*/genetics, Cisplatin/pharmacology ; Deoxycytidine/analogs & derivatives ; Deoxycytidine/pharmacology ; Humans ; Animals ; Cell Line, Tumor ; Mice ; Gemcitabine ; Xenograft Model Antitumor Assays ; DNA Repair ; Protein-Tyrosine Kinases |
| Περίληψη: | Cholangiocarcinoma (CCA) is a highly aggressive biliary malignancy with limited responses to existing treatments. Gemcitabine plus cisplatin (GC) remains the standard first-line chemotherapy for advanced disease, but its clinical efficacy is suboptimal, and drug resistance frequently emerges in patients. Through high-throughput synergistic drug screening, we identified PKMYT1 as a key synthetic lethal target regulating the chemosensitivity of cholangiocarcinoma cells. Functional validation confirmed that the PKMYT1 small-molecule inhibitor RP6306 exerts robust synthetic lethal effects when used in combination with gemcitabine or cisplatin. Data from colony formation assays and a series of cellular functional experiments showed that genetic or pharmacological inhibition of PKMYT1 substantially compromises DNA damage repair (DDR) and induces massive DNA double-strand breaks. Further mechanistic investigations revealed that PKMYT1 binds to Aldolase A (encoded by the ALDOA gene) and enhances its enzymatic activity, thereby upregulating CCA glycolysis levels and inducing lactate accumulation, which ultimately elevates the lactylation level of MRE11, accelerates DDR and consequently drives chemoresistance in CCA. Both cell-derived and patient-derived xenograft models verified that combined treatment with RP6306 and GC markedly inhibits tumor growth in vivo. Taken together, this work reveals that the PKMYT1-ALDOA-mediated protein lactylation pathway acts as a critical regulator of chemoresistance in CCA. Targeting PKMYT1 could reverse chemotherapy resistance and enhance therapeutic outcomes for advanced CCA, offering a promising combination strategy for clinical application. |
| Competing Interests: | Competing interests statement:The authors declare no competing interest. |
| Grant Information: | N/A Oncode Institute; W2411079 National natural science foundation of China; 82330095 National natural science foundation of China; 2403226 National natural science foundation of China; 2024ZZ1008 Shanghai Municipal Health Commission () |
| Contributed Indexing: | Keywords: PKMYT1; chemotherapy; cholangiocarcinoma; lactylation |
| Substance Nomenclature: | EC 2.7.11.1 (PKMYT1 protein, human) 0 (Gemcitabine) EC 3.1.- (MRE11 Homologue Protein) 0 (Membrane Proteins) Q20Q21Q62J (Cisplatin) EC 4.1.2.13 (Fructose-Bisphosphate Aldolase) EC 2.7.11.1 (Protein Serine-Threonine Kinases) 0W860991D6 (Deoxycytidine) EC 2.7.10.1 (Protein-Tyrosine Kinases) |
| Entry Date(s): | Date Created: 20260929 Date Completed: 20260929 Latest Revision: 20261009 |
| Update Code: | 20261009 |
| PubMed Central ID: | PMC13643129 |
| DOI: | 10.1073/pnas.2623500123 |
| PMID: | 42809391 |
| Βάση Δεδομένων: | MEDLINE |
| ISSN: | 1091-6490 |
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| DOI: | 10.1073/pnas.2623500123 |