Targeting MTAP increases PARP inhibitor susceptibility in triple-negative breast cancer through a feed-forward loop
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
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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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 2

MTAP deficiency/inhibition renders cells susceptible to PARPi.

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MTAP deficiency/inhibition renders cells susceptible to PARPi. (A) Pred...
(A) Predicted sensitivity to the indicated genotoxic agents for breast cancer with MTAP WT or deletion. (B–D) Tumor growth curves (B), tumor growth inhibition (C), and Kaplan-Meier survival curves (D) of PDX3 and PDX4 models treated with vehicle, olaparib (50 mg/kg), or veliparib (50 mg/kg). (E–H) Tumor growth inhibition and Kaplan-Meier survival curves of HCC70 (E and F) and PDX4 (G and H) xenograft models treated with olaparib (50 mg/kg), veliparib (50 mg/kg), or MTAPi (10 mg/kg), or the indicated combinations. (B, C, E, and G) Data are shown as the mean ± SD from 1 representative experiment of 5 mice per group. n = 10 mice per group in D, F, and H. P values are indicated. Significance was determined using (A) 2-sided Mann-Whitney U, (B) 2-way ANOVA, (C) unpaired t, (D, F, and H) log-rank (Mantel-Cox), or (E and G) 1-way ANOVA test.