Metabolic Enzyme Could Be the Answer to Using Lynparza in Broad Range of Tumors

Metabolic Enzyme Could Be the Answer to Using Lynparza in Broad Range of Tumors

Cancer cells often change their metabolism to support their fast growing rate. Researchers have now found that an enzyme involved in this mechanism, called PGAM1, is also required to activate DNA repair in cancer cells.

As a result, inhibiting PGAM1 could sensitize cancer cells to the FDA-approved ovarian cancer drug Lynparza (olaparib) and block tumor growth.

The study with the findings, titled “Phosphoglycerate mutase 1 regulates dNTP pool and promotes homologous recombination repair in cancer cells,” was published in The Journal of Cell Biology.

As the cells proliferate, small mistakes in DNA replication may occur. Cells have different mechanisms to correct these mistakes so the accurate genetic information can be kept. Because cancer cells have a high proliferation rate, they rely on the efficiency of these correction mechanisms for survival and growth.

Several cancers, such as breast, lung, and prostate cancers, have high levels of PGAM1, known for its role in different metabolic events that support rapid cancer cell proliferation. But researchers have now found that besides this function, PGAM1 is also involved in the regulation of one of the repair mechanisms, known as homologous recombination (HR) repair.

Inhibiting PGAM1 was found to impair this HR repair response, making cancer cells selectively more sensitive to chemotherapy drugs such as Platinol (cisplatin).

BRCA enzymes are essential for a correct HR repair mechanism function. Therefore, BRCA-mutant cancer cells rely on different DNA repair mechanisms. Lynparza is currently used to target BRCA-mutated cancers, targeting the PARP enzyme that is essential for the remaining repair mechanisms in these cells.

Consistently, when the researchers treated breast cancer mouse models with functional BRCA1 and BRCA2 genes with Lynparza, they found no effects. But when Lynparza was combined with a PGAM1 inhibitor, blocking both PARP-dependent and HR repair mechanisms, the researchers were able to suppress tumor growth.

These results suggested that Lynparza has the potential to treat a wider range of cancer types and not just cancers carrying BRCA1 or BRCA2 mutations.

“This suggests that PGAM1 inhibitors can sensitize 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,” Min Huang, senior author of the study, said in a press release.

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