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Review
. 2016 Apr:160:65-83.
doi: 10.1016/j.pharmthera.2016.02.003. Epub 2016 Feb 16.

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

Navnath S Gavande  1 , Pamela S VanderVere-Carozza  1 , Hilary D Hinshaw  2 , Shadia I Jalal  1 , Catherine R Sears  1 , Katherine S Pawelczak  3 , John J Turchi  4
Affiliations
Review

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

Navnath S Gavande et al. Pharmacol Ther. 2016 Apr.

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 that 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.

Keywords: Cancer; DNA damage; DNA repair; Radiation; Replication protein A.

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Conflict of interest statement

Conflict of interest

The authors declare that there are no conflicts of interest.

Figures

Fig. 1
Fig. 1
DNA damage response and repair. DNA damaged induced by the indicated insults are indicated by the magenta boxes. Pathways involved in responding to and repairing the damage along with current proteins being targeted are indicated.
Fig. 2
Fig. 2
Role of PARP inhibitors in DNA repair and synthetic lethality. PARP1 (red) binding to an endogenously induced SSB results in activation and auto ADP-ribosylation (gold triangles) which promotes efficient BER. In the presence of PARPi’s DNA replication (red arrows) generates a DSB with in HR proficient cells can be repaired to allow replication re-start and maintain cell viability while in HR deficient cells, the DSB persists resulting in cell death.
Fig. 3
Fig. 3
Structures and activities of several PARP inhibitors.
Fig. 4
Fig. 4
Molecular interactions of talazoparib (BMN673) (yellow) with hPARP1 (green and gray) (PDB code: 4UND). Interaction with amino acid side chains and structured water molecules are indicated with the dashed magenta lines and distances indicated in Å.
Fig. 5
Fig. 5
Structures and activity of NER inhibitors.
Fig. 6
Fig. 6
Schematic representation of the RPA heterotrimeric subunits (70, 32 and 14 kDa) and OB-fold domains (A–F). The DNA interactions sites are indicated by the red bars, subunit interaction sites by gold bars and domains associated with binding other proteins by the black bars.
Fig. 7
Fig. 7
Surface representation of RPA70 A and B domains (PDB code: 1FGU) with TDRL-505. TDRL-505 docked in domain A (cyan), domain B (wheat), and the interdomain region (green). ΔG suggests higher affinity of TDRL-505 for domain B and the interdomain region, whereas modest affinity for domain A.
Fig. 8
Fig. 8
NHEJ Pathway. Following a IR-induced DSB, the Ku dimer (green/magenta) engage the DNA terminus. Association and activation of DNA-PKcs (yellow) results in target protein phosphorylation of Artemis (orange) and autophosphorylation. Termini processing by Artemis and pol X family polymerases (not shown) is followed by ligation via DNA ligase IV/XRCC4 and XLF complex.
Fig. 9
Fig. 9
Structures and activity of DNA-PK, PNKP and Ligase IV inhibitors.
Fig. 10
Fig. 10
Structures and activity of MRN, ATM, ATR and Chk1/2 inhibitors.
Fig. 11
Fig. 11
Molecular interaction of Chk inhibitors A) Molecular interactions of MK-8776 with hChk1: MK-8776 is docked using predecessor X-ray crystal structure (PDB code: 3OT3) to delineate the key interactions. The N-1 moiety and exocyclic NH2 of the pyrazolo[1,5-a]pyrimidine binds to the Cys87 and water molecule in the hinge region, pyrazole moiety interacts with an array of ordered water molecules in the Chk1 specificity domain, piperidine amine makes several key interactions with acidic residues (Glu91 and Glu134) and a conserved water molecule and pyrazolo[1,5-a]pyrimidine moiety is surrounded by hydrophobic residues Leu136 and Leu137 (black dots).; B) Molecular interactions of CCT241533 with hChk2 (PDB code: 2XBJ): A planar and pseudotetracyclic structure formed due to intramolecular hydrogen bonding in between the phenolic hydroxyl and the quinazoline N-1, the phenolic hydroxyl binds to Met304 in the hinge region, quinazoline exocyclic amine makes contact with Glu308, pyrrolidine amine forms a charge-assisted hydrogen interaction with Asn352, two methoxy substituents occupying the solvent exposed region and quinazoline moiety is surrounded by hydrophobic residues Val234, Leu354, Ala247, Leu301 and Leu303 (some of them shown in black dots). Intermolecular and Intramolecular hydrogen bonds showed in magenta and orange dotted lines, respectively and distances indicated in Å.
Fig. 12
Fig. 12
Rad51 catalyzed homologous recombination repair. A leading strand replication block (purple box) stalls fork progression leading to the generation of single stranded DNA and binding of RPA (green trimer). Rad51 (red) replacement of RPA and association of BRCA2 (magenta) precedes homology driven recombination to by-pass the lesion and fork restart.
Fig. 13
Fig. 13
Structures and activity of Rad51 stimulator (RS-1) and inhibitors.
Fig. 14
Fig. 14
Structures and activity of BER inhibitors.
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