Prostate Cancer Heterogeneity: Discovering Novel Molecular Targets for Therapy

Highlights • Prostate cancer (PCa) shows a broad spectrum of biological and clinical behavior, which represents the epiphenomenon of an extreme genetic heterogeneity. • The AR and PI3K/Akt/mTOR signaling pathways are the two most frequently altered, representing therefore interestingly targets for therapy. • Recent studies have allowed to define the frequency of inactivating mutations of DNA repair genes (DRGs) in prostate cancer, taking into account the distinction between germline and somatic mutations, and recalling also the genetic diversity between localized disease and advanced castration resistant PCa. • Germline mutations in DNA repair genes (BRCA2, BRCA1, MSH2, HOXB13) have been related to an increased risk of developing PCa. • The PI3K/Akt pathway is the second most commonly genomic aberration hyperactivated in advanced PCa, after AR alterations. • The possibility of identifying driver mutations present at a specific stage of the disease, of classifying PCa based on specific molecular alterations, and of selecting the most appropriate treatment based on biomarkers predictors of response represent the foundations for future personalized medicine.