A triple-punch approach: methionine restriction enhances combination inhibitors in brain metastatic triple-negative breast cancer
Samyuktha Suresh, James M. Ford
Samyuktha Suresh, James M. Ford
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Commentary

A triple-punch approach: methionine restriction enhances combination inhibitors in brain metastatic triple-negative breast cancer

Abstract

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, presents a clinical challenge in developing effective treatment options. In this issue of the JCI, Zeng et al. demonstrate a provocative and promising therapeutic strategy for TNBC by leveraging the metabolic vulnerabilities presented by methylthioadenosine phosphorylase (MTAP) deletion to genotoxic stress inducers, such as poly (ADP-ribose) polymerase inhibitors (PARPi). They found that combining MTAP deletion or inhibition with PARPi was highly effective in brain metastatic TNBC where the methionine-limited environment further enhanced this combination. This approach underscores the importance of targeting metabolic vulnerabilities in the development of personalized cancer therapies.

Authors

Samyuktha Suresh, James M. Ford

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Figure 1

TNBC cells with MTAP deficiency possess impaired methionine metabolism that disrupts DNA repair.

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TNBC cells with MTAP deficiency possess impaired methionine metabolism t...
(A) In WT cells, the methyl donor SAM participates in various biological processes, including DNA repair. (B) TNBC cells lacking MTAP show disrupted methionine metabolism, which depletes SAM and impairs the recruitment of MRE11. Without MRE11, and in the context of a methionine-deplete environment such as in the brain, DSBs remains unrepaired. (C) In MTAP-deficient TNBC cells, PARPi activates METTL16, which further restricts SAM activity and compounds the effect of SAM on decreased DNA repair. SAH, S-adenosylhomocysteine; MTA, methylthioadenosine.