Use of poly ADP-ribose polymerase [PARP] inhibitors in cancer cells bearing DDR defects: the rationale for their inclusion in the clinic

Abstract

BackgroundDNA damage response (DDR) defects imply genomic instability and favor tumor progression but make the cells vulnerable to the pharmacological inhibition of the DNA repairing enzymes. Targeting cellular proteins like PARPs, which cooperate and complement molecular defects of the DDR process, induces a specific lethality in DDR defective cancer cells and represents an anti-cancer strategy. Normal cells can tolerate the DNA damage generated by PARP inhibition because of an efficient homologous recombination mechanism (HR); in contrast, cancer cells with a deficient HR are unable to manage the DSBs and appear especially sensitive to the PARP inhibitors (PARPi) effects.Main bodyIn this review we discuss the proof of concept for the use of PARPi in different cancer types and the success and failure of their inclusion in clinical trials.The PARP inhibitor Olaparib [AZD2281] has been approved by the FDA for use in pretreated ovarian cancer patients with defective BRCA1/2 genes, and by the EMEA for maintenance therapy in platinum sensitive ovarian cancer patients with defective BRCA1/2 genes. BRCA mutations are now recognised as the molecular targets for PARPi sensitivity in several tumors. However, it is noteworthy that the use of PARPi has shown its efficacy also in non-BRCA related tumors. Several trials are ongoing to test different PARPi in different cancer types. Here we review the concept of BRCAness and the functional loss of proteins involved in DDR/HR mechanisms in cancer, including additional molecules that can influence the cancer cells sensitivity to PARPi. Given the complexity of the existing crosstalk between different DNA repair pathways, it is likely that a single biomarker may not be sufficient to predict the benefit of PARP inhibitors therapies. Novel general assays able to predict the DDR/HR proficiency in cancer cells and the PARPi sensitivity represent a challenge for a personalized therapy.ConclusionsPARP inhibition is a potentially important strategy for managing a significant subset of tumors. The discovery of both germline and somatic DNA repair deficiencies in different cancer patients, together with the development of new PARP inhibitors that can kill selectively cancer cells is a potent example of targeting therapy to molecularly defined tumor subtypes.

Biological Subtypes of Triple-Negative Breast Cancer

“…Frequent loss of several other genes involved in BRCA1-dependent homologous recombination (HR) repair has been demonstrated in basal-like/triple-negative cancer, most likely contributing to BRCA1-like features [17]. Due to innovative treatment options, information about the BRCA1-like or 'BRCAness' status may have important clinical implications: A number of studies have shown that homologous recombination deficiency (HRD) sensitizes the tumor to DNA-damaging agents such as platinum compounds, or to poly(ADP-ribose)polymerase (PARP) inhibitors, or their combination [18][19][20]. Accordingly, biomarkers to identify and select patients with BRCA1-like ('BRCAness') signatures are urgently required.…”

Fighting tubulin-targeting anticancer drug toxicity and resistance

“…The lack of known specific molecular targets has led to extensive research to find possible vulnerabilities in TNBC. The biologic drugs already evaluated or under active research and that have shown antitumor activity in TNBC include angiogenesis inhibitors, PARP1 inhibitors, immune checkpoint inhibitors and AR antagonists, the latter used for the specific treatment of the luminal androgen receptor TNBC subtype that expresses high levels of AR (Lehmann et al 2015, Cerrato et al 2016, Hartkopf et al 2016. As a different approach, chemically modified taxanes have been, and are still, extensively being tested in clinical trials, alone or in combination with other chemotherapeutics.…”

DNA Mismatch Repair in Advanced Metastatic Prostate Carcinoma: Clinical Perspective

“…Moreover, these are being extensively investigated in multiple clinical trials. PARP inhibitors are undergoing trials in different tumor types including ovarian, breast, pancreatic, gastric, non-small cell lung cancer, melanoma, glioblastoma, and other cancers [19].…”