Non-small cell lung cancer (NSCLC) comprises the vast majority of all lung cancers, which is the leading cause of cancer-related deaths today. Despite this statistic, the availability of targeted therapeutics that effectively modulates the drivers of NSCLC is surprisingly low. Particularly for squamous cell lung carcinoma (SQCLC), a subtype of NSCLC, there are no successful targeted therapies to date, and thus, the identification and validation of molecular targets driving SQCLC are of high demand. The proposed project outlines the biochemical and cell-based investigation of APOBEC3B, a mutagenic cytidine deaminase known to be overexpressed in a wide array of cancers including SQCLC. The goal of this project is to better characterize APOBEC3B as a potential therapeutic target for SQCLC treatment. In understanding the molecular mechanisms of APOBEC3B-induced carcinogenesis, the proposed study aims to 1) biochemically and biophysically investigate APOBEC3B catalysis, nucleic acid binding, and structure, and 2) validate its association with SQCLC using a series of cell-based experiments. In the first aim, using recombinantly expressed and purified full-length APOBEC3B, a series of steady-state enzyme assays, electrophoretic mobility shift assays, and X-ray crystallography will be utilized to understand the biochemical basis of APOBEC3B mutagenic activity. In the second aim, a panel of SQCLC cell lines and normal lung cancer cell lines will be tested using overexpression and RNAi knockdown methodology to validate the association between APOBEC3B expression levels and carcinogenesis, in the context of SQCLC. Together, these aims will converge in understanding the molecular mechanisms of APOBEC3B-induced carcinogenesis and will provide novel insights into the development of targeted therapy strategies for SQCLC.
Targeted cancer therapies are a hallmark of modern medicine where treatments act to block very specific molecules that drive the induction of particular cancers. In this proposal, we aim to better understand the role of a commonly overexpressed DNA mutator, APOBEC3B, in causing squamous cell lung carcinoma (SQCLC), a form of lung cancer that affects a large population of smokers, to characterize it as a potential target for targeted cancer therapy. This study is compulsory for elucidating the molecular mechanisms of APOBEC3B-induced carcinogenesis and in the development of novel therapeutics to treat patients suffering from SQCLC.
