Validation of genetic vulnerabilities of telomerase-overexpressing prostate cancers

TERT, the gene encoding telomerase, is overexpressed in 85-90% of cancers, allowing these cancers to regenerate their telomeres and achieve cell immortality. TERT has been shown to be upregulated in prostate cancer, a prevalent malignancy worldwide, providing a model and reason for this research. Attempts have been made to target TERT directly to inhibit cancer cell growth, however they have not performed well in clinical trials. Synthetic dosage lethality (SDL) is a concept in which simultaneous overexpression of one gene with the inhibition of another partner gene results in cell death only when both conditions are met. Given that telomerase is overexpressed in many cancers, it is a promising target for SDL therapy.

Previous screens in the Vizeacoumar lab identified genes NDAP1, GPBP1, IFPB1, TMNA2, HDCS3, PM5SS, and DPA2S as potential SDL partners for TERT. The goal of this project was to identify the most promising gene candidates for further investigation Clonogenic assays with knockdowns of these genes using lentiviral shRNA were performed in TERT overexpressing and non-TERT overexpressing cell lines, with shRFP controls. Results of these assays have identified NDAP1 and GPBP1 to be the most effective SDL partners with TERT, showing selective lethality in TERT-overexpressing cell lines.