2. Academic Validation
  3. Metabolically inducing defects in DNA repair sensitizes BRCA-wild-type cancer cells to replication stress

Metabolically inducing defects in DNA repair sensitizes BRCA-wild-type cancer cells to replication stress

  • Sci Signal. 2024 Nov 12;17(862):eadl6445. doi: 10.1126/scisignal.adl6445.
Kenji Watanabe 1,  Tatsuro Yamamoto 1,  Tomoko Fujita 1,  Shinjiro Hino 2,  Yuko Hino 2,  Kanami Yamazaki 3,  Yoshimi Ohashi 3,  Shun Sakuraba 4 5,  Hidetoshi Kono 4 5,  Mitsuyoshi Nakao 2,  Koji Ochiai 6,  Shingo Dan 3,  Noriko Saitoh 1
Affiliations

Affiliations

  • 1 Division of Cancer Biology, Cancer Institute of JFCR, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
  • 2 Department of Medical Cell Biology, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto 860-0811, Japan.
  • 3 Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, 3-8-31 Ariake, Koto-ku, Tokyo 135-8550, Japan.
  • 4 Institute for Quantum Life Science, National Institutes for Quantum Science and Technology, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
  • 5 Department of Quantum Life Science, Graduate School of Science, Chiba University, 1-33 Yayoi-cho, Inage-ku, Chiba 265-8522, Japan.
  • 6 PhytoMol-Tech Inc., 3-14-3 Minami-Kumamoto, Chuo-ku, Kumamoto City, Kumamoto 860-0812, Japan.
PMID: 39531517 DOI: 10.1126/scisignal.adl6445
Abstract

Metabolic reprogramming from oxidative respiration to glycolysis is generally considered to be advantageous for tumor initiation and progression. However, we found that breast Cancer cells forced to perform glycolysis acquired a vulnerability to PARP inhibitors. Small-molecule inhibition of mitochondrial respiration-using glyceollin I, metformin, or phenformin-induced overproduction of the oncometabolite lactate, which acidified the extracellular milieu and repressed the expression of homologous recombination (HR)-associated DNA repair genes. These serial events created so-called "BRCAness," in which cells exhibit an HR deficiency phenotype despite lacking germline mutations in HR genes such as BRCA1 and BRCA2, and, thus, sensitized the Cancer cells to clinically available poly(ADP-ribose) polymerase inhibitors. The increase in lactate repressed HR-associated gene expression by decreasing histone acetylation. These effects were selective to breast Cancer cells; normal epithelial cells retained HR proficiency and cell viability. These mechanistic insights into the BRCAness-prone properties of breast Cancer cells support the therapeutic utility and Cancer cell-specific potential of mitochondria-targeting drugs.

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