An Insight on Novel Molecular Pathways in Metastatic Prostate Cancer: A Focus on DDR, MSI and AKT

Abstract

Prostate cancer is still one of the main causes of cancer-related death in the male population, regardless of the advancements in the treatment scenario. The genetic knowledge on prostate cancer is widely increasing, allowing researchers to identify novel promising molecular targets and treatment approaches. Genomic profiling has evidenced that DNA damage repair genes' alterations are quite frequent in metastatic, castration resistant prostate cancer and specific therapies can interfere with this pathway, showing promising activity in this setting. Microsatellite instability is gaining attention as it seems to represent a predictive factor of the response to immunotherapy. Furthermore, the PTEN-PI3K-AKT pathway is another possible treatment target being investigated. In this review, we explore the current knowledge on these frequent genomic alterations of metastatic prostate cancer, their possible therapeutic repercussions and the promising future treatments under evaluation.

Keywords: AKT; DDR; MSI; PARP inhibitors; PI3K; immunotherapy; mCRPC; prostate cancer.

Figure 1

Schematic figure representing the natural history of prostate cancer.

Figure 2

Schematic illustration of DDR pathways. Platinum compounds provoke intrastrand adducts and interstrand DNA crosslinks that can be repaired only by the activation of the NER, HR and NEHJ systems. PARPi inhibits the single-strand break repair mediated by BER and SSBR. Deficit in the mismatch repair leads to the increase of mutations and, consequently, neoantigens. This process is associated with a potential response to ICI. dMMR: deficit mismatch repair; HR homologous recombination; ICI: immune checkpoint inhibitor; NER: nucleotide excision repair; NEHJ: non-homologous end joining; PARPi: PARP inhibitor; SSBR, single-strand break repair.

Figure 3

Figure schematically representing the mechanisms of action of PARP inhibitors treatment for patients with BRCA-mutant prostate cancer. BRCA1 and BRCA2 genes have been suggested to encode proteins of pivotal importance to DNA homologous recombination repair processes.

Figure 4

Schematic figure of the PI2K/Akt pathway. Following RTKs binding to the growth factors, the PI3K signaling pathway is activated. Akt: protein kinase B; GRB2: growth factor receptor-bound protein 2; PDK1: phosphoinositide-dependent kinase-1; PTEN: phosphatase and tensin homologue.