2025 LCRF – Boehringer Ingelheim Early Investigator Award on Innovative Approaches Toward the Treatment of HER2-Driven Lung Cancer
Elizabeth Brunk, PhD
The University of North Carolina at Chapel Hill
Research Project:
Linking Structural DNA Variation to Therapeutic Response and Resistance in HER2-Mutated NSCLC
Summary:
Lung cancer remains one of the most difficult cancers to treat, and even with new targeted therapies, many patients eventually face relapse. A small but important group of patients (i.e., those whose tumors carry mutational changes in a gene called HER2) now have access to a new drug called zongertinib, the first treatment designed specifically for HER2-mutated lung cancer. While this is a major step forward, nearly all patients treated with zongertinib will develop resistance within months, and doctors currently have no way to predict who will respond or why the cancer returns.
Our research focuses on understanding how these cancers become resistant by studying a type of genetic change known as extrachromosomal DNA (ecDNA). EcDNAs are small, circular pieces of DNA that break away from chromosomes and carry extra copies of growth-promoting genes. Tumors with ecDNA are unusually aggressive because these DNA circles can multiply, disappear, and reappear as the cancer adapts to treatment, like a shape-shifting survival mechanism. We believe this elusive form of DNA may be a key reason some HER2-mutated lung cancers resist even the best available targeted therapies.
In this project, we will study how ecDNA changes when HER2-mutated lung cancer cells and tumors are treated with zongertinib, and whether these changes predict how patients will respond to therapy. We will use advanced imaging, single-cell sequencing, and patient data from UNC, Duke, and TEMPUS to determine how common ecDNA is in HER2-mutated lung cancer and whether its presence is linked to poor outcomes.
By revealing how ecDNA allows cancers to adapt and resist treatment, this work could lead to new ways to monitor, predict, and ultimately prevent drug resistance in patients with HER2-mutated non-small cell lung cancer. Although this research begins in the lab, its goal is deeply patient-centered: to help clinicians make more informed treatment decisions and give patients more time and better options.