DNA damage response inhibition‐based combination therapies in cancer treatment: Recent advances and future directions

Abstract

DNA molecules are subject to various lesions that can be detrimental to the cells. DNA damage response (DDR) pathways encompass a variety of mechanisms that cells employ in response to DNA damage. While DDR promotes genomic stability in normal cells, it also protects cancer cells from DNA lesions, particularly against exogenous DNA‐damaging agents. Therefore, DDR pathways can be exploited to account for resistance to chemotherapy and radiotherapy and have the potential to be targeted in cancer treatment. Apart from the poly (ADP‐ribose) polymerase (PARP) inhibitors used in BRCA‐mutant cancers, other DDR inhibitors are being developed and tested in clinical trials. Based on the synthetic lethality theory, combination therapies utilizing DDR inhibitors have been explored and are currently undergoing clinical trials, with promising results in cancer treatment. Combination therapies typically employ a DDR inhibitor to sensitize cancer cells to traditional chemotherapeutic agents, radiotherapy, immunotherapy, and even PARP inhibitors. Herein, we focus on recent advances in DDR inhibitor‐based combination therapies other than PARP inhibitors, explore the advantages and disadvantages of the strategies, and discuss the current challenges and future perspectives.

The novel SMYD3 inhibitor EM127 impairs DNA repair response to chemotherapy-induced DNA damage and reverses cancer chemoresistance

“…Interestingly, SMYD3 does not appear to be essential for normal development, as previously shown in SMYD3-KO mice [ 24 , 25 , 59 ], while it is overexpressed in a wide variety of cancers and is therefore involved in the development of these malignancies [ 16 , 17 , 60 ]. As such, treating SMYD3-overexpressing tumors with SMYD3is may help increase susceptibility to chemotherapy, while avoiding the side effects on normal cells that have been observed in clinical trials of other DDR inhibitors [ 61 ]. Moreover, the broad potential of SMYD3 inhibition is strengthened by our previous analysis of publicly available human cancer data from The Cancer Genome Atlas (TCGA) dataset indicating that SMYD3 mRNA levels have been found increased in around 30% of colorectal, pancreatic, and breast tumors [ 20 ].…”

OGG1 competitive inhibitors show important off-target effects by directly inhibiting efflux pumps and disturbing mitotic progression

“…Even if combined therapies using different inhibitors or dualtarget inhibitors have proven their efficacy in some cases (Chen et al, 2022), it is not possible to predict the potential benefit of these dual effects for the treatment of particular patients. In view of the results presented here, it could be tempting to speculate that the inhibitory effect of SU0268 and TH5487 on both the DNA repair protein OGG1 and efflux pumps could have a synergistic effect and improve the efficacy of chemotherapeutical drugs.…”

Signaling pathway evaluation of leading ATRi, PARPi and CDK7i cancer compounds targeting the DNA Damage Response using Causal Inference

“…These pathways were chosen because our DDR inhibitors target a specific protein in each of these pathways and resistance often involves compensation in one of these pathways. For example, PARPi resistance can develop due to restoration of the HR pathway (Chen et al ., 2022). This also enables the detection of insights of where the protein target is involved in the resistance mechanism of other compounds.…”

“…There are many cancer drugs in development which target the DNA damage response (DDR), following early successes of drugs such as olaparib. There are several challenges posed to the success of these inhibitors, including emergence of resistance, identification of biomarkers for patient selection and identification of combination therapies that improve efficacy without a concomitant increase in toxicity (Chen et al ., 2022). After the approval of PARP inhibitors (PARPi) and establishment of their clinical use, for example, resistance mechanisms such as reversion of the homologous recombination phenotype were uncovered (Lord and Ashworth, 2017; Baxter et al ., 2022).…”