State-of-the-art strategies for targeting the DNA damage response in cancer

Abstract

Genomic instability is a key hallmark of cancer that arises owing to defects in the DNA damage response (DDR) and/or increased replication stress. These alterations promote the clonal evolution of cancer cells via the accumulation of driver aberrations, including gene copy-number changes, rearrangements and mutations; however, these same defects also create vulnerabilities that are relatively specific to cancer cells, which could potentially be exploited to increase the therapeutic index of anticancer treatments and thereby improve patient outcomes. The discovery that BRCA-mutant cancer cells are exquisitely sensitive to inhibition of poly(ADP-ribose) polymerase has ushered in a new era of research on biomarker-driven synthetic lethal treatment strategies for different cancers. The therapeutic landscape of antitumour agents targeting the DDR has rapidly expanded to include inhibitors of other key mediators of DNA repair and replication, such as ATM, ATR, CHK1 and CHK2, DNA-PK and WEE1. Efforts to optimize these therapies are ongoing across a range of cancers, involving the development of predictive biomarker assays of responsiveness (beyond BRCA mutations), assessment of the mechanisms underlying intrinsic and acquired resistance, and evaluation of rational, tolerable combinations with standard-of-care treatments (such as chemotherapeutics and radiation), novel molecularly targeted agents and immune-checkpoint inhibitors. In this Review, we discuss the current status of anticancer therapies targeting the DDR.

FIG. 1 |. DNA damage response pathways being targeted in the clinic.

Specific types of DNA damage — mismatches due to replication, single-strand DNA breaks (SSBs) or double-strand DNA breaks (DSBs) — result in the activation of specific signalling and repair cascades. DNA damage response (DDR) pathways mitigate replication stress and repair DNA; thus, deficiencies in these pathways result in the accumulation of SSBs and DSBs and increased immunogenicity owing to the generation of neoantigens from mutant proteins. Poly(ADP-ribose) polymerase (PARP) enzymes are key to activating a host of downstream repair mechanisms and are primary proteins involved in SSB repair or base-excision repair (BER). The repair of DSBs occurs predominately through the rapid, error-prone non-homologous end joining (NHEJ) repair pathway in conjunction with the much slower higher-fidelity, error-free homologous recombination (HR) repair pathway. DNA replication is a necessary component of DNA repair and thus cell cycle regulation and replication stress responses are intertwined with DDR pathways. The kinases ATR and ATM have crucial roles in DDR signalling and in maintaining replication fork stability, while also working together via their downstream targets, CHK1 and CHK2, respectively, to regulate cell cycle control checkpoints. The kinase activity of DNA-PK is essential for NHEJ and V(D)J recombination. WEE1 is a distinct nuclear kinase that regulates mitotic entry and nucleotide pools in coordination with DDR. Drugs targeting these key components of the DDR pathways that are undergoing clinical testing are indicated. ATRIP, ATR-interacting protein; EXO1, exonuclease 1; H2AX, histone H2AX; MRN, MRE11, RAD50 and NBS1 complex; POLB, DNA polymerase-β; RPA, replication protein A; TOPBP1, DNA topoisomerase 2-binding protein.

FIG. 2 |. Timeline of key events leading to FDA approvals of PARP inhibitors in cancer medicine.

Landmark discoveries and advances in the development of poly(ADP-ribose) polymerase (PARP) inhibitors are indicated^,,,,–, together with the current approved indications for these agents in the USA and the EU. CR, complete remission; PR, partial remission.

FIG. 3 |. Mechanisms of resistance to PARP inhibitors.

Resistance of cancers to poly(ADP-ribose) polymerase (PARP) inhibitors can be inherent or acquired. The potential mechanisms of resistance are varied and can be multifactorial but centre around three main categories: restoration of homologous recombination (HR) repair activity through direct (genomic, epigenetic or post-translational changes in the HR machinery itself) or indirect mechanisms (signalling that increases the activity and/or expression of the HR machinery); replication stress mitigation, whereby the cancer cell slows the cell cycle and stabilizes replication forks; and mechanisms not currently assigned to a single DNA repair pathway-related process but still alter the response to PARP inhibition, such as mutations in PARP itself, genomic events that alter protein poly ADP-ribosylation (PARylation) and/or PARP trapping, upregulation of drug efflux pumps and loss of biomarkers of sensitivity to PARP inhibition, such as expression of Schlaffen 11 (SLFN11) and/or a epithelial-to-mesenchymal (EMT) signature. 53BP1, TP53-binding protein 1, AR, androgen receptor; HSP90, heat-shock protein 90; MDR, multidrug resistance protein; MLL3, histone-lysine N-methyltransferase 2C; MLL4, histone-lysine N-methyltransferase 2B; PARG, poly(ADP-ribose) glycohydrolase

FIG. 4 |. Biomarker-driven combination strategies to augment PARP inhibitor responses.

Cancers that are inherently homologous recombination deficient (HRD) or display ‘BRCAness’/‘HRDness’ are susceptible to poly(ADP-ribose) polymerase (PARP) inhibition (PARPi). Acquired PARP inhibitor resistance arises owing to the phenotypic rescue of homologous recombination (HR) or by mitigation of replication stress, and could potentially be overcome through combination of PARP inhibitors with ATR inhibition (ATRi) and/or inhibition of cell cycle checkpoint kinases (CHKi), such as CHK1. Selected oncogenic drivers and metabolic pathways specific to certain tumour types can drive HR activity to enable cancer cell survival and PARP inhibitor resistance. Therefore, HR-proficient cancer cells can be induced to become HRD through the concept of chemical HRDness by targeting these pro-survival pathways with different molecularly targeted agents, thereby engendering PARP inhibitor sensitivity. Given the rapidly growing number of rational combinations, functional biomarkers of HR, replication stress and PARP trapping are now urgently needed to provide guidance as to which combination should be used for which tumour type and at what time point. AR, androgen receptor; BET, bromodomain and extraterminal motif; DSB, double-strand DNA break; NHEJ, non-homologous end joining; SSBs, single-strand DNA breaks.