Previously Funded Research

Paul Stockhammer, MD, PhD

Yale University

Research Project:

Molecular determinants of tumor growth and therapeutic response in ERBB2-mutant lung cancer

Summary:

There are certain types of lung cancer that depend on the activity of specific genes, called oncogenes. One of these oncogenes in lung cancer is the erb-b2 receptor tyrosine kinase (ERBB2 or HER2), and ERBB2 mutations are found in approximately 1-4% of all non-small cell lung cancers.

Although targeted therapies are considered first-line standard therapy for many oncogene-driven lung cancers, treatment options for patients with ERBB2-mutated lung cancer are limited. Recently, specific drugs like trastuzumab deruxtecan (T-DXd) and zongertinib have been developed that are directed against ERBB2 and responses to these drugs have been observed in ERBB2-mutated lung cancers in patients. However, some tumors only respond poorly to treatment and ultimately all patients unfortunately develop therapy resistance resulting in cancer regrowth.

The underlying mechanisms involved in response and resistance to therapies in ERBB2-mutated lung cancer are largely unknown. Having such knowledge is critical for choosing the most effective treatment for individual patients. Furthermore, to date, T-DXd and zongertinib are the only FDA-approved therapies in ERBB2-mutated lung cancer and neither are first-line treatment options available for standard use.

We recently discovered that a category of genes called tumor suppressor genes (TSGs) are among the most frequently mutated genes in addition to ERBB2 in ERBB2-mutated lung cancers. In a small cohort of patients with ERBB2-mutated lung cancers who received chemotherapy, we found that those with tumors with additional TSG mutations had poor clinical outcomes. However, the underlying molecular mechanisms by which TSGs are involved in response and resistance to specific treatments including T-DXd and zongertinib are unknown.

In this proposed study, I will investigate the clinical features and outcomes among patients with ERBB2-mutated lung cancer whose cancers have TSG mutations included in a large database. I will investigate whether certain treatments work better in tumors with specific TSG mutations. Next, I will study the role of TSGs using a genetically engineered mouse model of ERBB2-mutant lung cancer. Specifically, I will investigate whether TSGs contribute to ERBB2-mutant lung cancer growth and sensitivity to T-DXd and zongertinib. I hypothesize that TSGs are functionally relevant and determine patterns of lung cancer growth and treatment responses in ERBB2-mutant lung cancer and that different TSGs will have different effects on sensitivity to TDXd or zongertinib. Overall, this work will shed light on the clinical and biological consequences of TSGs in ERBB2-mutant lung cancer and it will identify lung cancers that are associated with poor clinical outcomes to therapies. This proposed work will therefore contribute to a better understanding of response and resistance in patients with ERBB2-mutant lung cancer, which will ultimately help us to understand how to optimally treat individual patients with this disease.