Current Evidence and Future Perspectives about the Role of PARP Inhibitors in the Treatment of Thoracic Cancers

Abstract

In recent years, poly (ADP-ribose) polymerase (PARP) inhibition has become a promising therapeutic option for several tumors, especially for those harboring a BRCA 1–2 mutation or a deficit in the homologous recombination repair (HRR) pathway. Nevertheless, to date, PARP inhibitors are still not largely used for thoracic malignancies neither as a single agent nor in combination with other treatments. Recently, a deeper understanding of HRR mechanisms, alongside the development of new targeted and immunotherapy agents, particularly against HRR-deficient tumors, traced the path to new treatment strategies for many tumor types including lung cancer and malignant pleural mesothelioma. The aim of this review is to sum up the current knowledge about cancer-DNA damage response pathways inhibition and to update the status of recent clinical trials investigating the use of PARP inhibitors, either as monotherapy or in combination with other agents for the treatment of thoracic malignancies. We will also briefly discuss available evidence on Poly(ADP-Ribose) Glycohydrolase (PARG) inhibitors, a novel promising therapeutic option in oncology.

Keywords:

• lung cancer
• PARP inhibitors
• PARG inhibitors
• homologous recombination repair
• malignant pleural mesothelioma
• targeted treatment

Abbreviations

SCLC, Small Cell Lung Cancer; NSCLC, Non-Small Cell Lung Cancer; MPM, malignant pleural mesothelioma; EGFR, epithelial growth factor receptor; ALK, anaplastic lymphoma kinase; ROS1, c-ros oncogene 1; KRAS, Kirsten rat sarcoma virus (KRAS); BRAF, V-raf murine sarcoma oncogene homolog B1; HER2, human epidermal growth factor receptor; PARP, poly (ADP-ribose) polymerase; HRR, Homologous Recombination Repair; PARPi, poly (ADP-ribose) polymerase inhibitors; PARG, poly (ADP-ribose) glycohydrolase; PARGi, poly (ADP-ribose) glycohydrolas inhibitors; NAD, Nicotinamide Adenine Dinucleotide; BER, Base-Excision Repair; NER, Nucleotide-Excision Repair; MMR, Mismatch Repair; HR, Homologous Recombination; NHEJ, Non-Homologous End-Joining; PARP-1, poly (ADP-ribose) polymerase-1; PARP-2, poly (ADP-ribose) polymerase-2; MGMT, MethylGuanineDNA Methyltransferase; BRCA1, BReast CAncer gene 1; BRCA2, BReast CAncer gene 2; ERCC1, Excision repair cross-complementation group 1; LOH, Loss Of Heterozygosis; EGFR, Epithelial Growth Factor Receptor; ALK, Anaplastic Lymphoma Kinase; PFS, Progression Free Survival; ATM, Ataxia-Telangiectasia Mutated; ATR, Ataxia-Telangectasia and Rad3 related; GDSC, Genomics of Drug Sensitivity in Cancer; CRISPR, Clustered Regularly Interspaced Short Palindromic Repeats; CAS9, CRISPR Associated Protein 9; IC₅₀, Half Maximal Inhibitory Concentration; PTEM, Phosphatase and Tensin Homolog; TMZ, Temozolomide; GCI, Gemcitabine/Cisplatin/Iniparib; GC, Gemcitabine/Cisplatin; ORR, Overall Response Rate; OS, Overall Survival; HR, Hazard Ratio; CI, Confidence Interval; WES, Whole Exome Sequencing; H2AFX, H2A Histone Family Member X; CRT, Chemoradiotherapy; DLT, Dose Limiting Toxicity; MTD, Maximum Tolerable Dose; ICIs, Immune Checkpoint Inhibitors; TMB, Tumor Mutational Burden; STING, Stimulator of IFN Genes; PD-1, Programmed Death-protein 1; PD-L1, Programmed Cell Death Ligand-1; TPS, Tumor Proportion Score; DOR, Duration of Response; DDRi, DNA Damage Response Inhibitors; ED, Extended Disease; LS, limited stage; PDX, Patient-Derived Xenograft; cRT, Consolidative Radiation Therapy; c-GAS, Cyclic GMP–AMP synthase; cGAMP, Cyclic Guanosine monophosphate–Adenosine Monophosphate; dsDNA, Double Stranded DNA; TBK1, TANK Binding Kinase 1; IRF-3, Interferon Regulatory Factor 3; CHK1, Checkpoint Kinase; BAP1, BRCA1-Associated Protein-1; DCR, Disease Control Rate; TPS, Tumor Proportion Score; VEGF, Vascular Endothelial Growth Factor; SSB, Single-strand breaks; ISGs, IFN-stimulated genes; MHC, major histocompatibility complex; TCR, T cell receptor; NGS, Next Generation Sequencing.

Disclosure

Professor Rossana Berardi reports grants from Lilly, grants from MSD, grants from Otsuka, grants from BI, grants from GSK, grants from Italfarmaco, grants from Roche, grants from AZ, outside the submitted work. The authors report no other conflicts of interest in this work.