Gene Amplification: Novel Strategy Against Drug Resistance in HER2-Positive Breast Cancer

By: Hope Craig, MSPH
Posted: Wednesday, April 6, 2022

In the journal Nature Biotechnology, researchers at Yale Cancer Center shared findings of a therapeutic strategy to fight drug resistance in HER2-positive breast and ovarian cancers. The potential drug design platform, developed by Faye A. Rogers, PhD, and colleagues, treats tumor growth characterized by HER2 gene amplification, directly converting amplified oncogenic driver genes into excessive DNA damage. The strategy works by activating DNA damage response through the formation of triplex-forming oligonucleotides at specific sequences within the amplified genes.

“We will also focus our efforts on drug delivery, since inadequate bioavailability to the tumor can significantly impact therapeutic effect,” Dr. Rogers stated in a Yale Cancer Center press release.

This design overrules the cells’ own DNA damage response machinery, as the triple structures target HER2 to induce copy number–dependent DNA double-strand breaks and activate p53-independent apoptosis in HER2-positive cancer cells. As a result, the cancer cells are forced to die, whereas normal tissue experiences minimal toxicity, giving non-cancerous cells the opportunity for DNA repair and survival.

Dr. Rogers and colleagues are hopeful their new approach can be translated to assist patients with other types of cancers, as well, since more than 460 amplified genes have been identified to date across 14 cancer subtypes. “We plan to extend this platform, particularly focusing on cancers with limited precision medicine options…,” Dr. Rogers commented.

Disclosure: Full authors’ disclosures are available at www.nature.com.

Nature Biotechnology

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