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Yale Cancer Center Study Shows New Strategy to Fight Drug Resistance in HER2-Positive Breast and Ovarian Cancers

October 28, 2021

New findings by researchers at Yale Cancer Center demonstrate a novel strategy to treat tumor growth in breast and ovarian cancers characterized by HER2 gene amplification, an increase in the number of copies of a gene. Gene amplification is a frequent underlying cause in the development of multiple cancers. The results were reported online today in the journal Nature Biotechnology.

“Our findings are exciting as they offer a new option to fight breast and ovarian cancers as effectively as clinically utilized drugs now targeting the HER2 protein,” said Faye Rogers, PhD, Associate Professor of Therapeutic Radiology at Yale Cancer Center and senior author of the study. “A number of anticancer therapies have been developed to inhibit the protein products of amplified cancer driver genes, but have met drug resistance.”

The strategy of Rogers and her team was to develop a drug platform that directly targets the amplified gene and converts the amplified DNA in the cancer cells into excessive DNA damage. Researchers induced gene-specific DNA damage by forming triplex structures at specific sequences within the amplified genes. Gene copy number variations allow formation of multiple triplex structures in the cancer cells (excessive DNA damage) and not in healthy cells that lack gene amplification (minimal DNA damage). This approach hijacks the cells own DNA damage response machinery and allows normal cells to choose DNA repair and survival while forcing cancer cells to die. This reduces the potential for normal tissue toxicity.

Researchers are encouraged this discovery can be translated to help patients with other types of cancers. More than 460 amplified genes have been identified across 14 cancer subtypes.

“We plan to extend this platform, particularly focusing on cancers with limited precision medicine options,” added Rogers. “We will also focus our efforts on drug delivery, since inadequate bioavailability to the tumor can significantly impact therapeutic effect.”

Funding for this study was provided by grants from the NIH and a Breast Cancer Alliance Exceptional Project Grant.

Yale associate research scientist Meetu Kaushik Tiwari, PhD, is lead author of the study. Other Yale authors contributing to this research include: Daniel A. Colon-Rios, Hemanta C Rao Tumul, Yanfeng Liu, Elias Quijano, Adam Krysztofiak, Cynthia Chan, Eric Song, Demetrios T. Braddock, MD, PhD, Hee-Won Suh, PhD, and W. Mark Saltzman, PhD.

Submitted by Anne Doerr on October 26, 2021