DNA damage response in brain tumors: A Society for Neuro-Oncology consensus review on mechanisms and translational efforts in neuro-oncology

Abstract

DNA damage response (DDR) mechanisms are critical to maintenance of overall genomic stability, and their dysfunction can contribute to oncogenesis. Significant advances in our understanding of DDR pathways have raised the possibility of developing therapies that exploit these processes. In this expert-driven consensus review, we examine mechanisms of response to DNA damage, progress in development of DDR inhibitors in IDH-wild-type glioblastoma and IDH-mutant gliomas, and other important considerations such as biomarker development, preclinical models, combination therapies, mechanisms of resistance and clinical trial design considerations.

Keywords: DDR inhibitors; DNA damage response; DNA repair; glioma; radiation therapy.

Figure 1.

Overview of relevant DNA DNA damage response (DDR) pathways in response to standard of care therapies of radiation therapy and alkylating chemotherapy (temozolomide). Antitumor therapy can cause DNA damage via double-strand breaks (DSBs) or single-strand breaks (SSBs). In the setting of double-strand breaks, DNA-PK is a multi-enzyme complex consistent with DNA binding domains and catalytic subunit, and it regulates non-homologous end-joining (NHEJ), which can occur in the absence of sister chromatids (eg, G1 arrest). DSBs can also activate the ATM pathway, which includes downstream phosphorylation of proteins including CHK2 and p53. ATR can be activated by several genotoxic stresses, including SSBs, and it phosphorylates several targets. DNA DDR pathways lead to cell cycle arrest, and possible outcomes include apoptosis or successful DNA repair. Relevant DNA repair mechanisms and relevant molecular factors are listed at the bottom of the figure. Cell-cycle specific timing and kinetics of double-strand break repair mechanisms, homologous recombination (HR), and NHEJ, are highlighted. The balance of HR versus NHEJ repair mechanisms reflects factors such as whether a template strand exists for HR-mediated repair, chromatin accessibility, the presence of relevant co-occurring mutations such as BRCA1/2 deficiency, and the burden of DNA damage. Targets of therapies that are under active testing in neuro-oncology are shaded with color and bolded.

Figure 2.

(A, top) MGMT, when unmethylated and expressed, repairs TMZ-induced DNA damage by removing alkyl groups from guanine residues. (A, bottom) Methylation of the MGMT gene promoter silences the expression of MGMT. In this scenario, TMZ-induced DNA alkylation is less able to be removed by MGMT. In MMR-proficient tumor cells, this may trigger a futile cycle of MMR. (B) The active form of temozolomide, methyl diazonium ion, acts as a methyl donor at O⁶-methylguanine (O⁶MeG) adducts. If these alkylated lesions are not repaired by MGMT, MMR-proficient cells can undergo futile cycling of mismatch repair and subsequent cell death. In MMR-deficient cells, cells may proliferate and develop hypermutated phenotypes that may confer therapy resistance. Abbreviations: MGMT, O⁶-methylguanine-DNA methyltransferase; TMZ, temozolomide; Me3, methyl group; O⁶meG, O⁶-methylguanine; G, guanine; T, thymine; MMR, mismatch repair.

Figure 3.

Overview of non-homologous end joining repair (NHEJ). NHEJ repair occurs in the absence of a sister chromatid template. First, there is localization of the KU dimer to the double-strand break. KU recruits DNA-PK and there is subsequent recruitment of ARTEMIS to facilitate processing of DNA ends. There is subsequent activation of XRCC4, XLF, and ARTEMIS. The complex recruits endonucleases and polymerases to complete repair and join resected ends.

Figure 4.

Overview of select altered DNA damage repair pathways that have been reported in IDH-mutated gliomas. (R)-2HG-mediated inhibition of ALKBH is thought to sensitize IDH-mutant gliomas to alkylating agents (far left). Inhibition of the histone demethylase KDM4B by (R)-2HG sensitizes IDH-mutant gliomas to PARP inhibition (middle left) and depletes NAD + pools (middle right), rendering IDH-mutant gliomas vulnerable to DNA repaired by NAD+-dependent enzymes such as PARP. (R)-2HG inhibits BCAAs including BCAT1, which depletes glutathione pools and sensitizes IDH-mutant gliomas to oxidative stress (far right). Abbreviations: mIDH, mutant IDH; BCAA, branched-chain amino acids.

Figure 5.

Molecular pathways by which modulation of the DNA damage response (DDR) could potentiate immune processes. DDR modulating agents such as PARP inhibitors, ATM inhibitors, and ATR inhibitors may increase production of extrachromosomal double-stranded DNA (dsDNA) in the cytosol, especially in the setting of cytotoxic therapies such as radiation therapy that can cause double strange DNA breaks. Such cytosolic dsDNA can be detected by cGAS/STING to potentiate innate immune responses by stimulating type I interferon expression, antigen presentation, tumor-infiltrating lymphocyte recruitment, PDL1 expression, and improved responses to immune checkpoint blockade therapy. Alternatively, DDR modulation could drive tumor hypermutation, which may also have immune modulatory effects. Abbreviations: Ag, antigen; TILs, tumor-infiltrating lymphocytes; ICB, immune checkpoint blockade; DDR, DNA damage response.