How Leukemia Gene Mutations Impact Response to PARP Inhibitors

The mutated genes in question, TET2 and DNMT3A, each influence the efficacy of treatment in different ways.

Investigators have identified specific leukemia gene mutations and the mechanics behind their regulating of DNA repair and response to poly (ADP-ribose) polymerase (PARP) inhibitors, according to a study published in Cancer Research. The mutated genes in question, TET2 and DNMT3A, each influence the efficacy of treatment in different ways.

“The product of these genes affect how other genes are expressed including DNA damage repair genes,” said Tomasz Skorski, MD, PhD, DSc, in a press release. “What we have found is that patients with TET2 mutations are extremely sensitive to synthetic lethality triggered by PARP inhibitors. Meanwhile patients with the DNMT3A mutation are resistant. We also identified the mechanisms by which this occurs.”

Leukemia is typically treated with drugs that damage the DNA of both leukemia and normal cells. PARP inhibitors are a type of targeted therapy used to induce synthetic lethality—inactivation of 2 genes resulting in cell death where the inactivation of only 1 would not—in cancers carrying BRCA1/BRCA2 mutations, which are rare in leukemias.

“We designed a strategy so that we can take advantage of the fact that leukemia cells repair the DNA in more effective but different ways from normal cells,” Skorski said in the release. “One of the key elements is that we find the specific ways the leukemia cells from particular patients repair the DNA that’s damaged. The leukemia cells in patient A may repair DNA by using different mechanisms than in patient B. So, it’s important to identify how leukemia cells in both patient A and patient B repair DNA damage and what is different between normal cells in these patients and the leukemia cells.”

According to the investigators, these findings may be helpful in developing new personalized therapies tailored for patients with leukemias carrying TET2 mutations. A clinical trial, intended to further explore the application of this information, is currently being designed.

REFERENCE

Fels and Fox Chase researchers highlight roles of TET2 and DNMT3A mutations in personalized medicine-guided synthetic lethality against leukemia [news release]. EurekAlert; August 13, 2021. Accessed August 16, 2021. https://www.eurekalert.org/news-releases/925305