Zhang, Lingxin

Abstract Triple-negative breast cancer (TNBC) is an aggressive form of breast cancer with limited therapeutic strategy and unfavorable prognosis, especially for patients bearing brain metastasis. Here, we demonstrate that MTAP gene deletion or MTAP inhibition by MTAP inhibitor, MTDIA, sensitizes breast cancer cells to poly (ADP-ribose) polymerase (PARP) inhibitor (PARPi). Mechanistically, PARPi suppresses the expression of methionine adenosyltransferase 2A (MAT2A) by inducing METTL16 auto-inhibition mediated intron retention. Given that MAT2A and MTAP are key enzymes in methionine metabolism, the dual inhibition of MAT2A and MTAP disrupts methionine metabolism and leads to reduced s-adenosylmethionine. Dietary methionine restriction further boosts the combined anti-tumor efficacy of MTAP depletion/inhibition and PARPi. Most importantly, in brain metastatic TNBC, due to the natural low methionine environment in the brain, the combination of MTAP depletion/inhibition and PARPi confers significant therapeutic efficacy. Therefore, our findings provide a promising strategy for inhibiting primary or brain metastatic TNBC.