DNA repair targeted therapy: The past or future of cancer treatment?

Abstract

The repair of DNA damage is a complex process that relies on particular pathways to remedy specific types of damage to DNA. The range of insults to DNA includes small, modest changes in structure including mismatched bases and simple methylation events to oxidized bases, intra- and interstrand DNA crosslinks, DNA double strand breaks and protein-DNA adducts. Pathways required for the repair of these lesions include mismatch repair, base excision repair, nucleotide excision repair, and the homology directed repair/Fanconi anemia pathway. Each of these pathways contributes to genetic stability, and mutations in genes encoding proteins involved in these pathways have been demonstrated to promote genetic instability and cancer. In fact, it has been suggested all cancers display defects in DNA repair. It has also been demonstrated that the ability of cancer cells to repair therapeutically induced DNA damage impacts therapeutic efficacy. This has led to targeting DNA repair pathways and proteins to develop anti-cancer agents that will increase sensitivity to traditional chemotherapeutics. While initial studies languished and were plagued by a lack of specificity and a defined mechanism of action, more recent approaches to exploit synthetic lethal interaction and develop high affinity chemical inhibitors have proven considerably more effective. In this review we will highlight recent advances and discuss previous failures in targeting DNA repair to pave the way for future DNA repair targeted agents and their use in cancer therapy.

Germline mutation contribution to chromosomal instability

“…A strategy to cancer therapy that has been gaining traction in recent years is synthetic lethality (Kaelin 2005, Helleday et al 2008, Curtin 2012, Gavande et al 2016. Synthetic lethality is the circumstance in which genetic defects in two different genes or pathways together leads to cell death but when either occurred alone, is compatible with viability (Kaelin 2005, Curtin 2012.…”

“…Synthetic lethality is the circumstance in which genetic defects in two different genes or pathways together leads to cell death but when either occurred alone, is compatible with viability (Kaelin 2005, Curtin 2012. One of the successful examples to date is the application of poly(ADP-ribose) polymerase inhibitors (PARPis) to specifically kill BRCA1/2-deficient tumors (Bryant et al 2005, Curtin 2012, Gavande et al 2016, Lim & Ngeow 2016. PARP is a nuclear protein important for recognizing DNA damage and repairing DNA singlestrand breaks (SSBs) (Gavande et al 2016).…”

“…One of the successful examples to date is the application of poly(ADP-ribose) polymerase inhibitors (PARPis) to specifically kill BRCA1/2-deficient tumors (Bryant et al 2005, Curtin 2012, Gavande et al 2016, Lim & Ngeow 2016. PARP is a nuclear protein important for recognizing DNA damage and repairing DNA singlestrand breaks (SSBs) (Gavande et al 2016). It is proposed that inhibition of PARP prevents its release from damaged DNA, resulting in the accumulation of unrepaired SSBs that would give rise to DSBs, which is typically resolved by HR repair (Curtin 2012, Gavande et al 2016.…”

“…PARP is a nuclear protein important for recognizing DNA damage and repairing DNA singlestrand breaks (SSBs) (Gavande et al 2016). It is proposed that inhibition of PARP prevents its release from damaged DNA, resulting in the accumulation of unrepaired SSBs that would give rise to DSBs, which is typically resolved by HR repair (Curtin 2012, Gavande et al 2016. The lack of a functional HR repair mechanism in BRCA1/2-deficient cells renders vulnerability to cell death upon PARPi administration (Bryant et al 2005).…”

DNA Mismatch Repair in Advanced Metastatic Prostate Carcinoma: Clinical Perspective

“…More recently, a synthetic lethal therapeutic approach using PARP inhibitor therapy has been developed for BRCA mutant negative and HR deficient-related cancers (those with "BRCAness") [16]. And it is also suggested that defective HR secondary to BRCA1 and BRCA2 mutations may render cancer cells particularly sensitive to inhibition of singles stranded binding proteins (SSB) repair through inhibition of PARP [17]. Particularly, PARP inhibitors such as olaparib and niraparib exhibited significant antitumor efficacy in ovarian, breast, and PCa with dysfunctional HR [18].…”