Targeting MTAP increases PARP inhibitor susceptibility in triple-negative breast cancer through a feed-forward loop
Xiangyu Zeng, … , Liewei Wang, Zhenkun Lou
Xiangyu Zeng, … , Liewei Wang, Zhenkun Lou
Published July 1, 2025
Citation Information: J Clin Invest. 2025;135(13):e188120. https://doi.org/10.1172/JCI188120.
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Research Article Oncology

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

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.

Authors

Xiangyu Zeng, Fei Zhao, Xinyi Tu, Yong Zhang, Wen Yang, Jing Hou, Qi Jiang, Shouhai Zhu, Zheming Wu, Yalan Hao, Lingxin Zhang, Richard M. Weinshilboum, Kaixiong Tao, Liewei Wang, Zhenkun Lou

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Figure 11

MTAPi combined with low-dose PARPi profoundly benefits brain metastatic TNBC.

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MTAPi combined with low-dose PARPi profoundly benefits brain metastatic ...
(A–C) Representative in vivo bioluminescence imaging (A), quantification of radiance (B) prior to treatment or 21 days after treatment, and Kaplan-Meier survival curves (C) of intracardiac injection mouse models of MTAP WT HCC70 aggressive BrM cells, treated with vehicle, veliparib (10 mg/kg), or MTAPi (10 mg/kg) or their combination. (D–F) Representative in vivo bioluminescence imaging (D), quantification of radiance (E) prior to treatment or 18 days after treatment, and Kaplan-Meier survival curves (F) of intracranial injection mouse models of MTAP WT HCC70 aggressive BrM cells, treated with vehicle, veliparib (10 mg/kg), or MTAPi (10 mg/kg) or their combination. (G) Kaplan-Meier survival curves of PDX4 intracranial injection mouse models treated with vehicle, veliparib (10 mg/kg), or MTAPi (10 mg/kg) or their combination. (B and E) Data are shown as the mean ± SD from 1 representative experiment. n = 12 mice per group in C, F, and G. P values are indicated. Significance was determined using (B and E) 1-way ANOVA or (C, F, and G) log-rank (Mantel-Cox) test.