2021 VA Research Scholar Award Harold Bien, MD, PhD Stony Brook University/Northport VA Medical Center Stony Brook NY Research Summary Despite recent advances in therapy, lung cancer remains the leading cause of cancer deaths among US Veterans. Certain cancers have changes in their DNA genes that affect both how they grow and how they respond to treatments. Alterations in the KRAS gene are commonly found in lung cancers and targeted treatments against KRAS are still only in clinical trials. Understanding the biology of lung cancers with KRAS mutations could speed development of new treatments and identify those who will benefit from specific therapies. I will study individual cancer cells to better understand how KRAS mutations drive lung cancer to find opportunities for new treatments. I will also measure how differences between individual cancer cells in the same cancer correlate with response to treatments and survival. The cancer cells will come from lung cancer specimens removed from Veterans as part of their medical care This grant will support my growth as a lung cancer physician and researcher focused specifically on the US Veteran population as part of the NY metropolitan VA Oncology Research Group (NYmet VA ORG), a consortium of five VA facilities within the VA national Lung Precision Oncology Program. The data and samples we collect will be part of the larger NYmet VA ORG “natural history” project tracking and studying lung cancers from the incipient stage (during lung cancer screening) through diagnosis, treatment, and response. Technical Abstract Activating mutations in KRAS are found in 20 to 40% of lung cancers and not infrequently in combination with additional alterations in genes such as tumor suppressor TP53 or STK11. How activating KRAS mutations and/or co-mutations affect gene expression in both tumor cells and the cells in the surrounding microenvironment is not known. The impact, if any, of these mutations on intra-tumoral heterogeneity in gene expression is not known. Applying single cell RNA sequencing to resected lung adenocarcinoma samples from US Veterans, I will examine and compare the gene expression profiles of tumor cells from lung adenocarcinomas harboring either mutant and wild-type KRAS, and the expression profiles of cells in the surrounding microenvironment, including tumor infiltrating lymphocytes. In addition, I will determine whether KRAS mutational status affects the degree of intra-tumoral heterogeneity in gene expression, a known factor in survival and resistance to treatment. In sum, we hope to identify specific pathways affected by KRAS in both tumor and surrounding non-tumor cells that could be hypothesis-generating and learn use this knowledge to understand how resistance to KRAS specific therapies might be facilitated by pre-existing intra-tumoral heterogeneity.
