breast-cancer

Metabolic enzyme SIRT5 drives chemotherapy resistance in triple-negative breast cancer by rewiring energy pathways

Triple-negative breast cancer (TNBC) has the worst prognosis among breast cancer subtypes, partly because a significant fraction of patients don't respond to chemotherapy even at first treatment. This study used proteomics and metabolomics on pre-treatment biopsies from TNBC patients to identify what distinguishes chemoresistant from chemosensitive tumors before treatment even begins.

Chemoresistant TNBCs showed elevated oxidative phosphorylation (OXPHOS) and altered nucleotide metabolism, linked to overexpression of SIRT5 — a mitochondrial enzyme. Through gain/loss-of-function studies and isotope tracing, SIRT5 was shown to induce a coordinated metabolic switch that enables cells to survive chemotherapy. This switch also compromises the ATR checkpoint — a DNA damage response pathway — which may explain how these cells tolerate chemotherapy-induced DNA damage.

Identifying a pre-treatment biomarker (SIRT5 expression) and a targetable resistance mechanism in the same study is a compelling combination.

Key Findings

Pre-treatment proteomics and metabolomics distinguish chemoresistant from chemosensitive TNBC
Chemoresistant tumors exhibit elevated OXPHOS and altered nucleotide metabolism
SIRT5 (mitochondrial sirtuin) is overexpressed and drives the chemoresistance metabolic switch
SIRT5-induced metabolic changes compromise ATR DNA damage checkpoint activity
SIRT5 expression is a candidate predictive biomarker for de novo chemoresistance

Implications

SIRT5 inhibition could sensitize chemoresistant TNBC to standard chemotherapy. The pre-treatment biopsy proteomics approach offers a path to identifying patients unlikely to respond before committing to toxic regimens. The ATR checkpoint connection also suggests synthetic lethality with ATR inhibitors — a class of drugs in clinical development.

Caveats

Preprint — not peer reviewed. Based on abstract only. Biopsy cohort size not stated. Mechanistic studies likely cell line based — in vivo validation details unclear from abstract. SIRT5 inhibitors are not yet clinically available. ATR checkpoint deregulation finding needs detailed mechanistic validation.

Source: bioRxiv — 2026-04-09

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