Previously Funded Research

Team Science Co-Awardees

Principal Investigator: John Heymach, MD, PhD, University of Texas MD Anderson Cancer Center
Co-investigators:
Samir M. Hanash, MD, PhD, University of Texas MD Anderson Cancer Center
Michael Eck, MD, PhD, Harvard Medical School
John W. Lawson, PhD, NASA Ames Research Center
Heidi Greulich, PhD, Broad Institute of MIT & Harvard

Lung cancer is the leading cause of cancer-related death worldwide. A subset of patients with non–small cell lung cancer (NSCLC) have tumors driven by mutations in a gene called HER2. While recent approvals of HER2-targeted tyrosine kinase inhibitors (TKIs) have represented major progress, most patients eventually relapse because their tumors develop resistance. This proposal seeks to understand why resistance occurs and to develop new strategies to overcome it, with the goal of delivering more durable and effective treatments for patients with HER2-mutant lung cancer.

This research program consists of two complementary projects that address distinct but interconnected forms of resistance. Project 1 focuses on HER2-dependent resistance, in which additional changes arise within the HER2 protein itself that prevent drugs from working effectively. HER2 mutations are highly diverse, and different mutations respond differently to treatment. In Project 1, our team will systematically map which HER2 mutations drive resistance to current TKIs, determine how these mutations alter the structure of HER2, and use advanced computational modeling to predict drug response. These insights will be used to design and test new TKIs tailored to specific HER2 mutations, with the most promising candidates advanced through laboratory and animal studies toward future clinical trials.

Project 2 addresses a different but equally important problem: resistance that occurs even without new HER2 mutations. Many cancer cells survive treatment by entering a drug tolerant persister state. These cells can later evolve into fully resistant tumors. Our preliminary data show that these surviving cells display unique proteins on their cell surface that are rarely found on normal tissues. In HER2-mutant lung cancer models, proteins such as CD70, ALPP, and HER3 become highly expressed after treatment. These proteins represent attractive targets for immune-based therapies.

We will analyze tumor models and patient samples before treatment, during minimal residual disease, and at resistance to identify changes in gene expression, tumor cell identity, and cell-surface proteins. Using these data, we will prioritize targets that are both tumor-specific and broadly relevant. We will then test antibody-based therapies and engineered immune cells that recognize these targets, either alone or in combination with HER2-targeted drugs.

If these approaches work well in laboratory and animal studies, the results will directly support a doctor-led clinical study testing a HER3-targeted therapy, or similar treatments, in patients with HER2-mutant lung cancer who have already been treated with HER2-targeted pills.