Project 466522

Small-cell lung cancer (SCLC) is a highly aggressive and lethal type of lung cancer. Patients diagnosed with extensive-stage (ES), in which the cancer has spread to other parts of the body, are treated with platinum-based chemotherapy and only about 1 in 10 patients live to 5 years after diagnosis of ES-SCLC. Studies with patients have found that giving radiotherapy (RT) to the lung areas of ES-SCLC patients has increased duration of life. A promising strategy to enhance the effect of RT is to use new drugs that can make the radiation more powerful. We used a gene manipulation technology called CRISPR to examine 650 promising druggable targets and found that the loss of a gene known as Histone Deacetylase 3 (HDAC3) caused SCLC cells to be more sensitive to RT. However, how losing HDAC3 causes SCLC to be more sensitive to RT remains unknown. To understand the mechanism, we will test whether HDAC3 loss in SCLC increases the number of DNA double-strand breaks (DSBs) and persistence of DSBs induced by RT. We will use a technique called immunofluorescence staining to look at the number of DNA DSBs in SCLC cells with little to no HDAC3 protein. We will also introduce fluorescent reporters in these cells to see whether DSBs have been repaired. We will also test whether the RGFP966 drug, which inhibits HDAC3 protein, is suitable for future use in patients. We will examine the side effects and anti-cancer effects of the RGFP966 drug in combination with RT in laboratory models. Ultimately, we aim to enhance the effect of RT in SCLC by understanding how HDAC3 loss makes SCLC more sensitive to RT to understand if this approach and new drug can be used in future patient care.