Overcoming PARPi resistance: Preclinical and clinical evidence in ovarian cancer
Autor: | Giovanna Damia, Federica Guffanti, Francesco Bertoni, I. Colombo, M. Chiappa |
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Rok vydání: | 2020 |
Předmět: |
0301 basic medicine
Cancer Research DNA Repair DNA damage medicine.medical_treatment Poly ADP ribose polymerase Ubiquitin-Protein Ligases Angiogenesis Inhibitors Antineoplastic Agents Poly(ADP-ribose) Polymerase Inhibitors 03 medical and health sciences 0302 clinical medicine Downregulation and upregulation Antineoplastic Combined Chemotherapy Protocols medicine Humans Pharmacology (medical) Gene Immune Checkpoint Inhibitors Loss function Randomized Controlled Trials as Topic Pharmacology BRCA2 Protein Ovarian Neoplasms Chemotherapy business.industry medicine.disease Up-Regulation 030104 developmental biology Infectious Diseases Oncology Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female Homologous recombination business Ovarian cancer DNA Damage |
Zdroj: | Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy. 55 |
ISSN: | 1532-2084 |
Popis: | Ovarian cancer is the fifth cause of cancer-related deaths in women with high grade serous carcinoma (HGSOC) representing the most common histological subtype. Approximately 50 % of HGSOC are characterized by deficiency in homologous recombination (HR), one of the main cellular pathways to repair DNA double strand breaks and one of the well-described mechanisms is the loss of function of the BRCA1 or BRCA2 genes. Inhibition of the poly-ADP-ribose polymerase (PARP) is synthetic lethal with HR deficiency and the use of PARP inhibitors (PARPi) has significantly improved the outcome of patients with HGSOC with a greater benefit in patients with BRCA1/2 deficient tumors. However, intrinsic or acquired resistance to PARPi inevitably occurs in most HGSOC patients. Distinct heterogeneous mechanisms underlying the resistance to PARPi have been described, including a decrease in intracellular drug levels due to upregulation of multidrug efflux pumps, loss of expression/inactivating mutations in the PARP1 protein, restoration of HR and the protection of the replicative fork. Deciphering the molecular mechanisms of resistance to PARPi is of paramount importance towards the development of new treatment strategies and/or novel pharmacological agents to overcome this chemoresistance and optimize the treatment regimen for individual HGSOC patients. The current review summarizes the mechanisms underlying the resistance to PARPi, the available preclinical and clinical data on new combination treatment strategies (with chemotherapy, anti-angiogenic agents and immune checkpoint inhibitors) as well as agents under investigation which target the DNA damage response. |
Databáze: | OpenAIRE |
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