The DNA damage response (DDR) network and the mitogen-activated protein kinase (MAPK) signaling pathway are crucial mechanisms for the survival of all living beings. An accumulating body of evidence suggests that there is crosstalk between these two systems, thus favoring the appropriate functioning of multi-cellular organisms. On the other hand, aberrations within these mechanisms are thought to play a vital role in the onset and progression of several diseases, including cancer, as well as in the emergence of drug resistance. Here, we provide an overview of the current knowledge regarding alterations in the DDR machinery and the MAPK signaling pathway as well as abnormalities in the DDR/MAPK functional crosstalk in multiple myeloma, the second most common hematologic malignancy. We also present the latest advances in the development of anti-myeloma drugs targeting crucial DDR- and MAPK-associated molecular components. These data could potentially be exploited to discover new therapeutic targets and effective biomarkers as well as for the design of novel clinical trials. Interestingly, they might provide a new approach to increase the efficacy of anti-myeloma therapy by combining drugs targeting the DDR network and the MAPK signaling pathway.

The DNA-damage response (DDR) network and the immune system are significant mechanisms linked to the normal functioning of living organisms. Extensive observations suggest that agents that damage the DNA can boost immunity in various ways, some of which may be useful for immunotherapeutic applications. Indeed, the immune system can be activated by the DDR network through a number of different mechanisms, such as via (a) an increase in the tumor neoantigen burden, (b) the induction of the stimulator of interferon genes pathway, (c) the triggering of immunogenic cell death, (d) an increase in antigen presentation as a result of the augmented expression of the major histocompatibility complex type I molecule, (e) modification of the cytokine milieu in the tumor microenvironment, and (f) altered expression of the programmed cell death ligand-1. Together, the DDR network may improve the effect of immunostimulatory anticancer agents and provide a basis for devising more efficient treatment strategies, such as combinatorial therapies of DDR targeting drugs and immunomodulators. Here, the molecular mechanisms underlying the immune system’s activation by DDR are summarized, along with some of their possible uses in cancer treatment.

The DNA Damage Response (DDR) network and the mitogen-activated protein kinase (MAPK) signaling pathway are crucial mechanisms for the survival of all living beings. An accumulating body of evidence suggests that there is a crosstalk between these two systems, thus favoring the appropriate functioning of multi-cellular organisms. On the other hand, aberrations within these mechanisms are thought to play a vital role in the onset and progression of several diseases, including cancer, as well as in the emergence of drug resistance. Here, we provide an overview of the current knowledge regarding alterations in the DDR machinery and the MAPK signaling pathway, as well as abnormalities in the DDR-MAPK functional crosstalk in multiple myeloma, the second most common hematologic malignancy. We also present the latest advances in the development of anti-myeloma drugs targeting crucial DDR- and MAPK-associated molecular components. These data could potentially be exploited to discover new therapeutic targets and effective biomarkers, as well as for the design of novel clinical trials. Interestingly, they might provide a new approach to increase the efficacy of anti-myeloma therapy by combining drugs targeting the DDR network and the MAPK signaling pathway.

Background/Objectives: DNA damage response (DDR) is a network of molecular pathways associated with the pathogenesis and progression of several diseases, as well as the outcome of chemotherapy. Moreover, the intracellular redox status is essential for maintaining cell viability and controlling cellular signaling. Herein, we analyzed DDR signals and redox status in peripheral blood mononuclear cells (PBMCs) from patients with lung cancer with different response rates to platinum-based chemotherapy. Methods: Several DDR-associated signals and redox status, expressed as the GSH/GSSG ratio, were measured in two lung cancer cell lines (A549, H1299), two normal fibroblast cell lines (WS1, 1BR3hT), and PBMCs from 20 healthy controls and 32 patients with lung cancer at baseline (17 responders and 15 non-responders to subsequent platinum-based chemotherapy). Results: Higher levels of endogenous/baseline DNA damage, decreased GSH/GSSG ratios, and augmented apurinic/apyrimidinic sites, as well as lower nucleotide excision repair (NER) and increased interstrand cross-links (ICLs) repair efficiencies, were observed in lung cancer cell lines compared with normal ones (all p < 0.05). Moreover, PBMCs from patients with lung cancer showed reduced GSH/GSSG ratios, augmented apurinic/apyrimidinic sites, decreased NER and ICL repair capacities, and lower apoptosis rates, compared with healthy controls (all p < 0.001). Interestingly, PBMCs from patients who are responders are characterized by reduced GSH/GSSG ratios, augmented apurinic/apyrimidinic sites, decreased NER and ICL repair capacities, and higher apoptosis rates compared with patients who are non-responders (all p < 0.01). Conclusions: Together, DDR-associated parameters and redox status measured in PBMCs from patients with lung cancer at baseline are associated with the therapeutic benefit of platinum-based chemotherapy.

Accumulation of evidence highlighted the crosstalk between DNA damage repair and the immune system. Herein, we tested the hypothesis that in head and neck squamous cell carcinoma (HNSCC), the DNA repair capacity of patients’ PBMCs correlates with therapeutic response to immune checkpoint blockade. Following in vitro UVC irradiation, oxidative stress, apurinic/apyrimidinic (AP) lesions, endogenous/baseline DNA damage, and DNA damage repair efficiency were evaluated in three HNSCC (UM-SCC-11A, Cal-33, BB49) and two normal cell lines (RPMI-1788, 1BR-3h-T), as well as in peripheral blood mononuclear cells (PBMCs) from 15 healthy controls (HC) and 49 recurrent/metastatic HNSCC patients at baseline (8 responders, 41 non-responders to subsequent nivolumab therapy). HNSCC cell lines showed lower DNA repair efficiency, increased oxidative stress, and higher AP sites than normal ones (all p < 0.001). Moreover, patients’ PBMCs exhibited increased endogenous/baseline DNA damage, decreased DNA repair capacity, augmented oxidative stress, and higher AP sites than PBMCs from HC (all p < 0.001). Importantly, PBMCs from responders to nivolumab therapy showed lower endogenous/baseline DNA damage, higher DNA repair capacities, decreased oxidative stress, and reduced AP sites than non-responders (all p < 0.05). Together, we demonstrated that oxidative stress status and DNA repair efficiency in PBMCs from HNSCC patients are correlated with the response to immune checkpoint blockade.

The DNA Damage Response (DDR) network is an essential machinery for maintaining genomic integrity, with DDR defects being implicated in cancer initiation, progression, and treatment resistance. Moreover, oxidative stress, an imbalance between reactive oxygen species production and antioxidant defense, can significantly impact cell viability, leading to cell death or survival. Herein, we tested the hypothesis that DDR-related signals and redox status measured in multiple myeloma (MM) cell lines correlate with the sensitivity to genotoxic insults. At baseline and following irradiation with Ultraviolet C (UVC; 50 J/m²) or treatment with melphalan (100 μg/mL for 5 min) DDR-related parameters, redox status expressed as GSH/GSSG ratio and apurinic/apyrimidinic sites were evaluated in a panel of eleven human MM cell lines and one healthy B lymphoblastoid cell line. We found that MM cell lines with increased apoptosis rates displayed significantly higher levels of endogenous/baseline DNA damage, reduced GSH/GSSG ratio, augmented apurinic/apyrimidinic lesions, decreased nucleotide excision repair and interstrand crosslinks repair capacities, and highly condensed chromatin structure. Taken together, these findings demonstrate that DDR-related parameters and redox status correlate with the sensitivity of MM cells to DNA-damaging agents, specifically melphalan, and, if further validated, may be exploited as novel sensitive/effective biomarkers.