Predictors and Modulators of Synthetic Lethality: An Update on PARP Inhibitors and Personalized Medicine

Abstract

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven to be successful agents in inducing synthetic lethality in several malignancies. Several PARP inhibitors have reached clinical trial testing for treatment in different cancers, and, recently, Olaparib (AZD2281) has gained both United States Food and Drug Administration (USFDA) and the European Commission (EC) approval for use in BRCA-mutated advanced ovarian cancer treatment. The need to identify biomarkers, their interactions in DNA damage repair pathways, and their potential utility in identifying patients who are candidates for PARP inhibitor treatment is well recognized. In this review, we detail many of the biomarkers that have been investigated for their ability to predict both PARP inhibitor sensitivity and resistance in preclinical studies as well as the results of several clinical trials that have tested the safety and efficacy of different PARP inhibitor agents in BRCA and non-BRCA-mutated cancers.

ME1 Regulates NADPH Homeostasis to Promote Gastric Cancer Growth and Metastasis

“…When several other homologous genes serving overlapping functions were shut down by inhibitors, the cells would experience lethal strike (4,6,10). Genetic and pharmacologic studies have evidenced the therapeutic exploit of collateral deletion in the tumorsuppressive loci (4,(10)(11)(12). One notable example is that hemizygous deletion of TP53 in colorectal cancer necessarily led to high vulnerability to inhibition of the neighboring gene POLR2A (5).…”

Advances in ovarian cancer therapy

“…in: [ 72 ]). Also, other tumor-specific homologous recombination defects may be potentially exploited, such as somatic BRCA mutations, mutations in ATM, ATR, RAD51, and others [ 73 , 74 ]. First PARP inhibitor approved for clinical use was olaparib [ 75 ].…”

Small-Molecule Inhibitors Targeting DNA Repair and DNA Repair Deficiency in Research and Cancer Therapy

“…The possibility to take advantage of this pharmacologically induced synthetic lethality was tested in clinical trials since 2003 (Yap et al, 2011), and a decade later PARP inhibitors olaparib (2014) and later rucaparib (2016) were approved for the treatment of advanced, chemotherapy resistant ovarian cancer in patients with BRCA1 or BRCA2 germline mutations, and niraparib (2017) for treatment of platinum-sensitive recurrent ovarian, fallopian tube, and primary peritoneal cancers (see (Murata et al, 2016) for a comprehensive review on PARP inhibitors currently in various stages of clinical trials).…”

“…While approximately 15% of ovarian cancer patients with BRCA -deficient tumors remain disease free for more than 5 years from the beginning of the olaparib therapy (Ledermann et al, 2016), many patients develop PARP inhibitor resistance within the first year, which limits the effectiveness of the therapy (Incorvaia et al, 2017; Lupo and Trusolino, 2014; Murata et al, 2016). Several mechanisms were suggested for the emergence of resistance to PARP inhibitors.…”