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

Area of Science:

• Oncology
• Molecular Biology
• Cancer Metabolism

Background:

• Triple-negative breast cancer (TNBC) is an aggressive subtype with limited treatment options.
• PARP inhibitors (PARPi) show efficacy in BRCA-mutated breast cancers, but their use in TNBC is restricted by low mutation frequency.
• The role of methylthioadenosine phosphorylase (MTAP) in TNBC treatment resistance is not well understood.

Purpose of the Study:

• To investigate the role of MTAP deletion in TNBC sensitivity to genotoxic agents, particularly PARPi.
• To elucidate the underlying molecular mechanisms linking MTAP, methionine metabolism, and DNA repair in TNBC.
• To explore the therapeutic potential of combining MTAP inhibition with PARPi for TNBC treatment.

Main Methods:

• Analysis of a clinical cohort of metastatic TNBC patients.
• In vitro and in vivo studies assessing the effects of MTAP deficiency or inhibition on TNBC cell lines and tumor models.
• Investigation of the METTL16-MAT2A axis, s-adenosylmethionine (SAM) levels, and DNA repair pathways (MRE11 methylation and recruitment).

Main Results:

• MTAP deletion was identified as a sensitizer to genotoxic agents in metastatic TNBC.
• MTAP deficiency or inhibition increased TNBC susceptibility to PARPi.
• Targeting MTAP disrupted methionine metabolism, depleted SAM, and impaired PARPi-induced DNA repair by affecting MRE11 methylation and recruitment.
• Brain metastatic TNBC showed enhanced benefit from the combination therapy due to the brain's low methionine environment.

Conclusions:

• MTAP deficiency creates a vulnerability in TNBC that synergizes with PARPi.
• A feedback loop exists between methionine metabolism and DNA repair via SAM, presenting a novel therapeutic target.
• Combining PARPi with MTAP deficiency or inhibition represents a promising therapeutic strategy for TNBC, especially brain metastases.