Background: Radiotherapy and adjuvant androgen deprivation therapy have historically been the first treatment choices for prostate cancer but treatment resistance often limits the capacity to effectively manage the disease. Therefore, alternative therapeutic approaches are needed. Here, the efficacies of radiotherapy and targeting the pro-survival cell signaling components epidermal growth factor receptor (EGFR), phosphoinositide 3-kinase (PI3K), and mammalian target of rapamycin (mTOR), with their respective inhibitors are compared. Materials and Methods: The cytotoxic effects of inhibitors of PI3K and mTOR (NVP-BEZ235) and EGFR (AG-1478), and X-RAYS, were evaluated in prostate cell lines (LNCaP: cancer; DU145: cancer; BPH-1: benign prostatic hyperplasia; 1542N: apparently “ normal” ) using a colony forming assay. The cells were exposed to a range of X-ray doses or varying concentrations of the inhibitors, to obtain cell survival curves from which relative sensitivities (RS) of the tumor cell lines were derived as the ratio of their sensitivities to that of the “ normal” cell line. Results: The LNCaP cells trended to be more sensitive to X-RAYS and AG-1478 exposure than 1542N cells, with RSvalues of 1. 65± 0. 48 (P=0. 1644) and 1. 37± 0. 22 (P=0. 0822), respectively. NVPBEZ235 emerged as very cytotoxic in all tumor cell lines, yielding RS-values of 3. 69± 0. 83 (DU145; P=0. 0025), 8. 80± 1. 73 (LNCaP; P<0. 0001), and 8. 76± 1. 70 (BPH-1; P=0. 0011). Conclusion: These findings demonstrated that targeted therapy, specifically that using NVP-BEZ235, might result in a more effective treatment modality for prostate cancer than conventional radiotherapy.