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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| Published in: | The Journal of clinical investigation Vol. 135; no. 13; pp. 1 - 18 |
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| Main Authors: | , , , , , , , , , , , , , , |
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| Language: | English |
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American Society for Clinical Investigation
01.07.2025
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| ISSN: | 1558-8238, 0021-9738, 1558-8238 |
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| Abstract | 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. |
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| AbstractList | 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. 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.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. 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. Targeting MTAP confers TNBC to PARP inhibitors |
| Audience | Academic |
| Author | Yang, Wen Zhang, Lingxin Wu, Zheming Tao, Kaixiong Weinshilboum, Richard M. Wang, Liewei Tu, Xinyi Hou, Jing Lou, Zhenkun Zeng, Xiangyu Zhao, Fei Jiang, Qi Zhu, Shouhai Hao, Yalan Zhang, Yong |
| AuthorAffiliation | 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 4 Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, and 5 Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China 7 Analytical Instrumentation Center, Hunan University, Changsha, China 2 College of Biology, Hunan University, Changsha, China 3 Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA 8 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA 6 Department of Breast Surgery, Guizhou Provincial People’s Hospital, Guiyang, China |
| AuthorAffiliation_xml | – name: 1 Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China – name: 3 Department of Oncology, Mayo Clinic, Rochester, Minnesota, USA – name: 2 College of Biology, Hunan University, Changsha, China – name: 6 Department of Breast Surgery, Guizhou Provincial People’s Hospital, Guiyang, China – name: 5 Department of Breast and Thyroid Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China – name: 4 Department of Radiation Oncology, Hubei Cancer Hospital, Tongji Medical College, and – name: 8 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA – name: 7 Analytical Instrumentation Center, Hunan University, Changsha, China |
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| CitedBy_id | crossref_primary_10_1038_s41598_025_13361_0 crossref_primary_10_1172_JCI193171 |
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| Keywords | Oncology Breast cancer Amino acid metabolism DNA repair Therapeutics |
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| SubjectTerms | 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 |
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| Title | Targeting MTAP increases PARP inhibitor susceptibility in triple-negative breast cancer through a feed-forward loop |
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