Drugging the Cancers Addicted to DNA Repair

Abstract

Defects in DNA repair can result in oncogenic genomic instability. Cancers occurring from DNA repair defects were once thought to be limited to rare inherited mutations (such as BRCA1 or 2). It now appears that a clinically significant fraction of cancers have acquired DNA repair defects. DNA repair pathways operate in related networks, and cancers arising from loss of one DNA repair component typically become addicted to other repair pathways to survive and proliferate. Drug inhibition of the rescue repair pathway prevents the repair-deficient cancer cell from replicating, causing apoptosis (termed synthetic lethality). However, the selective pressure of inhibiting the rescue repair pathway can generate further mutations that confer resistance to the synthetic lethal drugs. Many such drugs currently in clinical use inhibit PARP1, a repair component to which cancers arising from inherited BRCA1 or 2 mutations become addicted. It is now clear that drugs inducing synthetic lethality may also be therapeutic in cancers with acquired DNA repair defects, which would markedly broaden their applicability beyond treatment of cancers with inherited DNA repair defects. Here we review how each DNA repair pathway can be attacked therapeutically and evaluate DNA repair components as potential drug targets to induce synthetic lethality. Clinical use of drugs targeting DNA repair will markedly increase when functional and genetic loss of repair components are consistently identified. In addition, future therapies will exploit artificial synthetic lethality, where complementary DNA repair pathways are targeted simultaneously in cancers without DNA repair defects.

Targeting DNA repair: the genome as a potential biomarker

“…The trial met its primary endpoint, as PFS was significantly longer in the BRCA mutant group (hazard ratio 0.27, 95% CI 0.16-0.44, P < 0.0001) and BRCA WT LOH high group (hazard ratio 0.62, 95% CI 0.42-0.90, P = 0.011) than in the BRCA WT LOH low subgroup. Response rates were higher in the BRCA mutant group (80%, 95% CI 64-91) than in the BRCA WT LOH high group (29%; 95% CI 20-40) and in the in the BRCA WT LOH low group (10%; 95% CI [4][5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20]. Interestingly, in those who did respond, median response durations were similar in the BRCA mutant LOH high group (9.2 months, 95% CI 6.4-12.9) and BRCA WT LOH high groups (10.8 months, 95% CI 5.7-not reached), and both were higher (P = 0.013 and P = 0.022, respectively) than in the LOH low subgroup (5.6 months, 95% CI 4.6-8.5).…”

Polymorphism of genes encoding proteins of DNA repair vs. occupational and environmental exposure to lead, arsenic and pesticides

“…W toku ewolucji wykształciły się mechanizmy detoksykacji szkodliwych substancji i systemy naprawy uszkodzonego DNA. Systemy naprawy DNA, takie jak naprawa bezpośrednia (DNA direct repair -DDR), naprawa błędnie sparowanych nukleotydów (DNA mismatch repair -MMR), naprawa przez wycinanie zasad (base excision repair -BER) lub nukleotydów (nucleotide excision repair -NER) czy naprawa dwuniciowych pęknięć DNA [1,2], chronią człowieka przed uszkodzeniami DNA indukowanymi przez ksenobiotyki (tab. 1).…”

“…Innym istotnym polimorfizmem w aspekcie naraże-nia na ołów jest polimorfizm genu XRCC3 (X-ray repair cross-complementing protein group 3 -białko biorące udział w naprawie DNA przez rekombinację homologiczną) (rs861539). Białko XRCC3, obok białka RAD51, uczestniczy w tworzeniu kompleksów nukleoproteinowych i ich stabilizacji w naprawie DNA przez rekombinację homologiczną [1]. Polimorfizm ten polega na tranzycji cytozyny (C) do tyminy (T), czego efektem jest substytucja aminokwasów Thr214Met (tab.…”

Werner syndrome helicase is a selective vulnerability of microsatellite instability-high tumor cells

“…Defects in components of the DNA repair machinery, such as BRCA1/2 mutations or impaired 48 DNA mismatch repair (MMR), are a common characteristic of tumor cells, accelerating the 49 accumulation of DNA mutations or chromosomal aberrations that are required for neoplastic 50 transformation (Kinzler and Vogelstein 1997). Plasticity of genome stability pathways permits 51 tumor cells to tolerate the loss of individual DNA repair genes and leads to synthetic lethality (SL) 52 upon targeting the compensating repair mechanism (Nickoloff, Jones et al 2017). The first 53 clinically approved drugs exploiting such a SL interaction are Poly(ADP-Ribose) Polymerase 54 (PARP) inhibitors for therapy of BRCA1/BRCA2-deficient tumors (Kaufman, Shapira-Frommer et 55 al.…”