Molecular mediators of disparate outcomes experienced by patients of African ancestry with lung cancer - PROJECT SUMMARY Lung cancer causes 1 in 5 deaths from cancer in the United States – more than any other malignancy. The burden of lung cancer deaths disproportionately impacts Black/African Americans for reasons that cannot be completely explained by social elements of health. Moreover, African Americans are chronically underrepresented in clinical trials and large-scale molecular profiling studies, suggesting potential unidentified mechanisms of therapeutic resistance. In preliminary studies, we determined ancestral composition of tumor cell lines and patient tumors using genomic profiling, and we found numerous molecular alterations associated with genomic ancestry. Notably, both cell lines and primary tumors from patients of European ancestry exhibited higher EGFR phosphorylation than those from patients of African ancestry. EGFR inhibitors are first-line treatments for patients with EGFR mutant lung cancer, despite minimal or even zero enrollment of African Americans in underlying clinical trials. EGFR phosphorylation remained significantly different when analyzing only EGFR mutant tumors. We detected no difference in EGFR mutation frequency based on patient ancestry. However, EGFR-mutant tumors from patients of African ancestry harbored a higher rate of additional mutations in oncogenes that are typically mutually exclusive with EGFR mutations, suggesting that EGFR mutation may be an insufficient oncogenic driver in this population. Critically, these observed molecular differences corresponded with a lack of EGFR inhibitor toxicity in cell lines from patients of African ancestry. In contrast, tumors/cell lines from patients of African ancestry exhibited elevated activation of DNA damage response pathways and heightened sensitivity to multiple DNA damage response inhibitors. This study will evaluate the hypothesis that heritable, ancestry-associated molecular features may contribute to disparate outcomes by influencing response to specific therapeutic modalities. We will evaluate this hypothesis by completing the following Specific Aims: Aim 1 will determine how EGFR signaling differs based on patient genetic ancestry. Aim 2 will quantify the interplay between EGFR activation, co-mutations, ancestry, and treatment outcomes. Aim 3 will identify novel therapeutic strategies that are more effective for patients of African ancestry. Together, these studies will provide critical insight into mechanisms underlying disparities in lung cancer outcomes and facilitate the development of therapeutic regimens to benefit patients with lung cancer.
