PGAM1 inhibitors sensitize tumors to lynparza (Olaparib) treatment.
The drug lynparza (Olaparib), which is approved for the treatment of ovarian cancer with BRCA mutations, has the potential to treat a broader range of cancer types, a recent study suggests.
The metabolic enzyme phosphoglycerate mutase 1 (PGAM1) helps cancer cells repair DNA, causing tumors to become desensitized to lynparza therapy.
In a study published in the Journal of Cell Biology, investigators found that a PGAM1 inhibitor may help boost the efficacy of lynparza by re-sensitizing the tumors to treatment.
In order to synthesize the materials that cancer cells require for rapid growth, they often alter their metabolic pathway. PGAM1 regulates multiple metabolic pathways, and there are abnormally high levels of this enzyme in cancers, such as breast cancer, lung cancer, and prostate cancer.
For the study, the investigators injected mice with human breast cancer cells containing functional BRCA1 and BRCA2 genes to form tumors. When lynparza was used alone, it had no efficacy on the tumors. However, when lynparza was combined with a PGAM1 inhibitor, it impaired both homologous recombination and PARP-dependent DNA repair, resulting in a significant suppression of tumor growth.
When PGAM1 was inhibited, the cancerous cells synthesized fewer deoxyribonucleotide triphosphates (dNTPs), which are the building blocks of DNA, according to the authors.
“This suggest that PGAM1 inhibitors can sensitive cancers to PARP inhibitors such as [lynparza], thereby expanding the benefits of PARP inhibitors to BRCA1/2-proficient cancers, particularly triple-negative breast cancers that currently lack effective therapies,” said author Min Huang.