Targeting MTAP increases PARP inhibitor susceptibility in triple-negative breast cancer through a feed-forward loop

Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of...

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Veröffentlicht in:	The Journal of clinical investigation Jg. 135; H. 13; S. 1 - 18
Hauptverfasser:	Zeng, Xiangyu, Zhao, Fei, Tu, Xinyi, Zhang, Yong, Yang, Wen, Hou, Jing, Jiang, Qi, Zhu, Shouhai, Wu, Zheming, Hao, Yalan, Zhang, Lingxin, Weinshilboum, Richard M., Tao, Kaixiong, Wang, Liewei, Lou, Zhenkun
Format:	Journal Article
Sprache:	Englisch
Veröffentlicht:	United States American Society for Clinical Investigation 01.07.2025
Schlagworte:	5'-Methylthioadenosine phosphorylase Animals Antineoplastic drugs Biomarkers Brain Neoplasms - drug therapy Brain Neoplasms - genetics Brain Neoplasms - secondary BRCA1 protein Breast cancer Cancer Cancer therapies Cell Line, Tumor Chemotherapy Cyclin-dependent kinases DNA damage DNA methylation DNA repair DNA Repair - drug effects Drug dosages Female Gene deletion Genotoxicity Health aspects Humans Kinases Medical prognosis Metabolism Metastases Metastasis Methionine Methionine Adenosyltransferase - genetics Methionine Adenosyltransferase - metabolism Methyltransferases - genetics Methyltransferases - metabolism Mice Mice, Knockout MRE11 protein Mutation Neoplasm Proteins - antagonists & inhibitors Neoplasm Proteins - genetics Neoplasm Proteins - metabolism Oncology Oncology, Experimental Patients Poly(ADP-ribose) polymerase Poly(ADP-ribose) Polymerase Inhibitors - pharmacology S-Adenosylmethionine S-Adenosylmethionine - metabolism Therapeutics Toxicity Transferases Triple Negative Breast Neoplasms - drug therapy Triple Negative Breast Neoplasms - enzymology Triple Negative Breast Neoplasms - genetics Triple Negative Breast Neoplasms - metabolism Triple Negative Breast Neoplasms - pathology China Oncology Breast cancer Amino acid metabolism DNA repair Therapeutics
ISSN:	1558-8238, 0021-9738, 1558-8238
Online-Zugang:	Volltext
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Zusammenfassung:	Triple-negative breast cancer (TNBC) represents the most malignant subtype of breast cancer. The clinical application of PARP inhibitors (PARPi) is limited by the low frequency of BRCA1/2 mutations in TNBC. Here, we identified that MTAP deletion sensitized genotoxic agents in our clinical cohort of metastatic TNBC. Further study demonstrated that MTAP deficiency or inhibition rendered TNBC susceptibility to chemotherapeutic agents, particularly PARPi. Mechanistically, targeting MTAP that synergized with PARPi by disrupting the METTL16-MAT2A axis involved in methionine metabolism and depleting in vivo s-adenosylmethionine (SAM) levels. Exhausted SAM in turn impaired PARPi-induced DNA damage repair through attenuation of MRE11 recruitment and end resection by diminishing MRE11 methylation. Notably, brain metastatic TNBC markedly benefited from a lower dose of PARPi and MTAP deficiency/inhibition synergy due to the inherently limited methionine environment in the brain. Collectively, our findings revealed a feed-forward loop between methionine metabolism and DNA repair through SAM, highlighting a therapeutic strategy of PARPi combined with MTAP deficiency/inhibition for TNBC.
Bibliographie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23 Authorship note: XZ and FZ contributed equally to this work and are co–first authors.
ISSN:	1558-8238 0021-9738 1558-8238
DOI:	10.1172/JCI188120