Cancer cells expressing the AID protein are particularly susceptible to treatments that modulate the activity of the DNA repair protein RAD51, according to preclinical-trial studies from Cyteir Therapeutics.
The company presented its findings in a poster session April 3 at the American Association of Cancer Research (AACR) Annual Meeting in Washington. It was titled “RAD51 and AICDA define a new synthetic lethal interaction that is targetable in multiple tumor types.”
The notion that mutations allow tumors to form — but also provide researchers with specific ways of killing them — is called synthetic lethality. In this case, synthetic does not refer to man-made, but rather to the mutated cells that make up a tumor.
For instance, scientists are developing PAPR inhibitors to treat cancers linked to BRCA gene mutations, which make it likely a woman will develop cancer.
When BRCA genes involved in DNA repair are faulty, tumor cells rely on another repair mechanism. PARP inhibitors block the mechanism, called PARP, without harming cells that lack BRCA mutations.
“The recent success of PARP inhibition as a DNA repair target has focused the field on the next set of synthetic lethal pairs, and our studies elucidate RAD51-AID as a novel target,” Donald F. Corcoran, president and chief executive officer of Cyteir, said in a news release. “This new preclinical data supports the continued development of selective small molecules that take advantage of this novel synthetic lethal pair. We will continue to optimize and study our lead compounds in order to identify a clinical candidate for cancer this year, and we further intend to evaluate whether our approach could be synergistic with PARP inhibition.”
Previous research has shown that aytidine deaminase (AID) drives DNA damage and is a biomarker of it. In cancer cells, activating AID leads to a higher mutation rate. This prompts the cells to recruit the DNA repair protein RAD51 to correct the mutations and survive.
Inhibiting RAD51 blocks cancer cells’ ability to repair the overwhelming majority of DNA damage, Cyteir researchers found. This triggers a mitotic catastrophe — cell death from cells dividing too early.
Preventing RAD51 from reaching the nuclei of AID-positive cells in mice injected with human leukemia and lymphoma led to strong cytotoxicity in the cells — but not in AID-negative cells.
“These in vivo preclinical studies demonstrate that RAD51 modulation selectively induces cell death in AID-expressing cancer cells,” said Kevin D. Mills, PhD, chief scientific officer of Cyteir. “Our small-molecule RAD51 modulators continue to demonstrate potent, selective effects on disease-causing cells in vitro and in vivo while remaining well tolerated in preclinical animal models of leukemia and lymphoma. We look forward to exploring the full potential of this therapeutic approach in multiple tumor types.”
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