Targeting DNA Damage Response Research Articles

Abstract 5039: Development of a prostate cancer PDX model radioresistant to PSMA targeted radionuclide therapy

Abstract Prostate cancer is the second most common cancer diagnosis worldwide and the fifth leading cause of cancer related death among men. Lutetium Lu 177 vivivotide tetraxetetan was recently approved by the FDA for treatment of prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. However, not all patients respond to treatment and combination therapies may improve outcomes. One approach is to combine targeted radionuclide therapy with inhibitors targeting DNA damage response pathways such as ATM/ATR inhibitors to enhance the radiosensitivity of the cancer cells. Currently, models used to study radioresistance in prostate cancer are based on cancer cell lines or cell-line derived xenograft models, but these models do not account for the heterogenous and complex biology of the disease. To overcome this issue, we aimed at developing a radioresistant PSMA positive prostate cancer patient-derived xenograft (PDX) model based on the ST1273 model (XenoSTART). ST1273 originates from a sixty-five-year-old Hispanic male that did not receive treatment prior to sampling. The model is characterized by overexpression of androgen receptor and PSMA. Tumors were implanted in nude mice and radioresistance was induced by external beam radiation therapy (3 × 2Gy per cycle) until tumor growth was unresponsive to the treatment. Flow cytometry were applied to evaluate if altered proliferation rate or changes in the tumor microenvironment (TME) convers the resistance. Out of five initially treated tumors, one tumor re-occurred after 19 days. Repeating the treatment led to an initial decrease in tumor volume but the growth delay was reduced to 12 days. A third treatment rendered the tumor resistant as tumor growth was unaffected. Current evidence confirms that radioresistance was maintained when passaging, and PSMA expression was unaffected. Next, we tested whether the tumor would also withstand targeted radionuclide therapy. Animals implanted with parental or radioresistant ST1273 tumors were treated with Lu177-PSMA-617 (5MBq, QW x2). The treatment reduced tumor size in both tumor types, but significantly less in the resistant model. Moreover, parental tumors had a significantly slower recurrence of 45 days compared to the resistant tumors that relapsed 24 days after the first dosing. Flow cytometry analysis of control and treated tumors (parental and radioresistant) showed that the radioresistance might be attributed to alterations in the cell cycle control. Altogether, we developed a PDX prostate cancer model that is resistance to external beam radiation and PSMA targeted radionuclide therapy. This model will allow us to further characterize radioresistance and evaluate combinatorial therapy in a clinically relevant model. Citation Format: Maria Thaysen, Esben Christensen, Rikke N. Nielsen, Michael Wick, Mette M. Wessel, Lotte K. Kristensen, Sebastian Gnosa, Carsten H. Nielsen. Development of a prostate cancer PDX model radioresistant to PSMA targeted radionuclide therapy. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5039.

Leveraging homologous recombination repair deficiency in sarcoma.

Personalised oncology is at the forefront of cancer research. The goal of personalised oncology is to selectively kill cancer cells while minimising side effects on normal tissue. This can be achieved by identifying and targeting cancer vulnerabilities that distinguish it from normal cells. Many cancers are deficient in high-fidelity DNA repair pathways that maintain genomic stability, such as homologous recombination (HR). Such cancers are highly sensitive to targeted therapies that induce DNA damage or inhibit DNA repair pathways. A notable example and a poster child of personalised oncology are PARP1/2 inhibitors (PARPi) that selectively kill HR-deficient (HRD) cancer cells by preventing repair of DNA gaps or single-strand breaks (SSBs) (Slade, 2020). Inhibitors of cell cycle checkpoints such as CHK1 and WEE1 can also eliminate HRD cancers by pushing cancer cells through the cell cycle despite unrepaired DNA damage and causing death by mitotic catastrophe (Groelly etal, 2022). PARPi have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancer but other cancer types with an HRD signature (HRDness) may also respond to PARPi treatment. Planas-Paz etal (2023) now show that many sarcomas show HRDness and respond to PARP1/2 and WEE1 inhibitors, thus offering a new personalised oncology approach for this treatment-refractory cancer.

Homologous Recombination Defects and Mutations in DNA Damage Response (DDR) Genes Besides BRCA1 and BRCA2 as Breast Cancer Biomarkers for PARP Inhibitors and Other DDR Targeting Therapies.

Homologous recombination repair (HRR) is the cellular mechanism for error-free repair of double strand DNA (dsDNA) breaks. Cancer cells with mutations in both alleles of genes encoding for proteins involved in HRR, such as BRCA1 and BRCA2, have defects in the repair process. As a result, these cells repair dsDNA breaks with alternative mechanisms, such as non-homologous end joining. In breast cancers with germline mutations in BRCA1 and BRCA2 genes, HRR defects result in sensitivity to PARP inhibitors, drugs that interfere with the function of PARP enzyme and promote trapping of the enzyme on DNA and stalling of the process of repairing single strand breaks. HRR defects also lead to sensitivity to DNA damaging chemotherapy due to the inability of cells to repair chemotherapy induced DNA lesions. Besides germline mutations in BRCA1 and BRCA2, somatic mutations in these genes or germline and somatic mutations or other genetic and epigenetic alterations of other genes involved in homologous recombination (HR) may produce HRR defects leading to sensitivity to PARP inhibitors. However, studies are less conclusive, a fact that may relate to the common lack of bi-allelic loss of function in these cases, as opposed to cancers with germline BRCA1 or BRCA2 defects that usually acquire bi-allelic loss of function. In addition, there is heterogeneity between the different HRR genes and the severity of the resulting HRR defects, as measured by HR defect assays. This review article examines the landscape of HRR gene mutations in breast cancer and the possible therapeutic implications of HRR defects other than germline BRCA1 and BRCA2 mutations for targeted therapies. Identification of a wider range of breast cancers with HRR defects may expand the subset of patients that derive benefit from PARP inhibitors and other DDR-targeting drugs in the clinic.

The evolving role of DNA damage response in overcoming therapeutic resistance in ovarian cancer.

Epithelial ovarian cancer (EOC) is treated in the first-line setting with combined platinum and taxane chemotherapy, often followed by a maintenance poly (ADP-ribose) polymerase inhibitor (PARPi). Responses to first-line treatment are frequent. For many patients, however, responses are suboptimal or short-lived. Over the last several years, multiple new classes of agents targeting DNA damage response (DDR) mechanisms have advanced through clinical development. In this review, we explore the preclinical rationale for the use of ATR inhibitors, CHK1 inhibitors, and WEE1 inhibitors, emphasizing their application to chemotherapy-resistant and PARPi-resistant ovarian cancer. We also present an overview of the clinical development of the leading drugs in each of these classes, emphasizing the rationale for monotherapy and combination therapy approaches.

Targeting DNA damage response pathways in cancer.

Cells have evolved a complex network of biochemical pathways, collectively known as the DNA damage response (DDR), to prevent detrimental mutations from being passed on to their progeny. The DDR coordinates DNA repair with cell-cycle checkpoint activation and other global cellular responses. Genes encoding DDR factors are frequently mutated in cancer, causing genomic instability, an intrinsic feature of many tumours that underlies their ability to grow, metastasize and respond to treatments that inflict DNA damage (such as radiotherapy). One instance where we have greater insight into how genetic DDR abrogation impacts on therapy responses is in tumours with mutated BRCA1 or BRCA2. Due to compromised homologous recombination DNA repair, these tumours rely on alternative repair mechanisms and are susceptible to chemical inhibitors of poly(ADP-ribose) polymerase (PARP), which specifically kill homologous recombination-deficient cancer cells, and have become a paradigm for targeted cancer therapy. It is now clear that many other synthetic-lethal relationships exist between DDR genes. Crucially, some of these interactions could be exploited in the clinic to target tumours that become resistant to PARP inhibition. In this Review, we discuss state-of-the-art strategies for DDR inactivation using small-molecule inhibitors and highlight those compounds currently being evaluated in the clinic.

Therapeutic Targeting of DNA Damage Repair in the Era of Precision Oncology and Immune Checkpoint Inhibitors.

Cancer manifestation is a multistep process involving accumulation of various genetic and epigenetic changes that results in oncogenic "hallmarks of cancer" processes including genomic instability. Exploitation of aberrant DNA-damage response (DDR) mechanisms in cancer is in part a goal of many therapeutic strategies, and recent evidence supports the role of targeting DDR in modulating the tumor immune microenvironment to enhance immunotherapeutic response. Improved cancer profiling, including next-generation and whole-genome mutational sequencing of tumor tissue, as well as circulating nucleic acids, has enhanced our understanding of the genetic and epigenetic molecular mechanisms in tumorigenesis and will become fundamental to precisely target tumors and achieve cancer control. With the successes of poly(ADP-ribose) polymerase inhibitors (PARPi) and immunotherapies, the intersection of DDR molecular machinery and corresponding antitumor immune response has gained much interest with a focus on achieving therapeutic synergy using DNA damage-targeting agents and immunotherapy. In this review, we provide a bench-to-bedside overview of the fundamentals of DDR signaling and repair as they relate to cancer therapeutic strategies including novel DDR-targeting agents. We also discuss the underlying mechanisms that link DDR signaling to antitumor immunity and immunotherapy efficacy, and how this knowledge can be used to improve precision medicine approaches in the treatment of cancer.

Targeting DNA damage response as a potential therapeutic strategy for head and neck squamous cell carcinoma.

Cells experience both endogenous and exogenous DNA damage daily. To maintain genome integrity and suppress tumorigenesis, individuals have evolutionarily acquired a series of repair functions, termed DNA damage response (DDR), to repair DNA damage and ensure the accurate transmission of genetic information. Defects in DNA damage repair pathways may lead to various diseases, including tumors. Accumulating evidence suggests that alterations in DDR-related genes, such as somatic or germline mutations, single nucleotide polymorphisms (SNPs), and promoter methylation, are closely related to the occurrence, development, and treatment of head and neck squamous cell carcinoma (HNSCC). Despite recent advances in surgery combined with radiotherapy, chemotherapy, or immunotherapy, there has been no substantial improvement in the survival rate of patients with HNSCC. Therefore, targeting DNA repair pathways may be a promising treatment for HNSCC. In this review, we summarized the sources of DNA damage and DNA damage repair pathways. Further, the role of DNA damage repair pathways in the development of HNSCC and the application of small molecule inhibitors targeting these pathways in the treatment of HNSCC were focused.

Sensitization of Patient-Derived Colorectal Cancer Organoids to Photon and Proton Radiation by Targeting DNA Damage Response Mechanisms.

Simple SummaryRadiotherapy plays an important role in the treatment of colorectal cancer (CRC). Approximately one-third of patients with rectal cancer show a pathological complete response upon total neoadjuvant treatment. Patient-derived CRC organoids were investigated regarding their radiotherapeutic treatment response—both in terms of conventional photon irradiation, the combination thereof with chemotherapy, as well as proton irradiation. By inhibition of an important sensor molecule for DNA damage, which has been shown to be activated upon irradiation, radioresistant organoids could be resensitized.Pathological complete response (pCR) has been correlated with overall survival in several cancer entities including colorectal cancer. Novel total neoadjuvant treatment (TNT) in rectal cancer has achieved pathological complete response in one-third of the patients. To define better treatment options for nonresponding patients, we used patient-derived organoids (PDOs) as avatars of the patient’s tumor to apply both photon- and proton-based irradiation as well as single and combined chemo(radio)therapeutic treatments. While response to photon and proton therapy was similar, PDOs revealed heterogeneous responses to irradiation and different chemotherapeutic drugs. Radiotherapeutic response of the PDOs was significantly correlated with their ability to repair irradiation-induced DNA damage. The classical combination of 5-FU and irradiation could not sensitize radioresistant tumor cells. Ataxia-telangiectasia mutated (ATM) kinase was activated upon radiation, and by inhibition of this central sensor of DNA damage, radioresistant PDOs were resensitized. The study underlined the capability of PDOs to define nonresponders to irradiation and could delineate therapeutic approaches for radioresistant patients.

Targeting DNA damage response components induces enhanced STING-dependent type-I IFN response in ATM deficient cancer cells and drives dendritic cell activation

ABSTRACT The concept of exploiting tumor intrinsic deficiencies in DNA damage repair mechanisms by inhibiting compensatory DNA repair pathways is well established. For example, ATM-deficient cells show increased sensitivity to the ATR inhibitor ceralasertib. DNA damage response (DDR)-deficient cells are also more sensitive to DNA damaging agents like the DNA crosslinker pyrrolobenzodiazepine (PBD) SG-3199. However, additional antitumor benefits from targeting the DDR pathways, which could operate through the activation of the innate immune system are less well studied. DNA accumulation in the cytosol acts as an immunogenic danger signal, inducing the expression of type-I interferon (IFN) stimulated genes (ISGs) by the activation of the cGAS-STING pathway. Here, we demonstrate that ATM −/− FaDu tumor cells have higher basal expression of ISGs when compared to WT cells and respond to ceralasertib and PBD SG-3199 by inducing higher levels of ISGs in a cGAS-STING-dependent manner. We show that sensitive tumor cells treated with ceralasertib and PBD SG-3199 activate dendritic cells (DCs) via a type-I IFN-dependent mechanism. However, STING deficiency in tumor cells does not prevent DC activation, suggesting that transactivation of the STING pathway occurs within DCs. Furthermore, depletion of the cytosolic DNA exonuclease TREX1 in tumor cells increases DC activation in response to PBD SG-3199-treated tumor cells, indicating that an increase in tumor-derived cytosolic DNA may further enhance DC activation. In summary, in this study, we show that ceralasertib and PBD SG-3199 treatment not only intrinsically target tumor cells but also extrinsically increase tumor cell immunogenicity by inducing DC activation, which is enhanced in ATM-deficient cells.

Nodus Oncology launches for DNA damage response targets

Nodus Oncology launches for DNA damage response targets

Targeting the DNA Damage Response Pathways and Replication Stress in Colorectal Cancer.

PurposeGenomic instability is a hallmark of cancer and targeting DNA damage response (DDR) is emerging as a promising therapeutic strategy in different solid tumors. The effectiveness of targeting DDR in colorectal cancer has not been extensively explored.Experimental DesignWe challenged 112 cell models recapitulating the genomic landscape of metastatic colorectal cancer with ATM, ATR, CHK1, WEE1, and DNA-PK inhibitors, in parallel with chemotherapeutic agents. We focused then on ATR inhibitors (ATRi) and, to identify putative biomarkers of response and resistance, we analyzed at multiple levels colorectal cancer models highly sensitive or resistant to these drugs.ResultsWe found that around 30% of colorectal cancers, including those carrying KRAS and BRAF mutations and unresponsive to targeted agents, are sensitive to at least one DDR inhibitor. By investigating potential biomarkers of response to ATRi, we found that ATRi-sensitive cells displayed reduced phospho-RPA32 foci at basal level, while ATRi-resistant cells showed increased RAD51 foci formation in response to replication stress. Lack of ATM and RAD51C expression was associated with ATRi sensitivity. Analysis of mutational signatures and HRDetect score identified a subgroup of ATRi-sensitive models. Organoids derived from patients with metastatic colorectal cancer recapitulated findings obtained in cell lines.ConclusionsIn conclusion, a subset of colorectal cancers refractory to current therapies could benefit from inhibitors of DDR pathways and replication stress. A composite biomarker involving phospho-RPA32 and RAD51 foci, lack of ATM and RAD51C expression, as well as analysis of mutational signatures could be used to identify colorectal cancers likely to respond to ATRi.

Model-based translation of DNA damage signaling dynamics across cell types

Interindividual variability in DNA damage response (DDR) dynamics may evoke differences in susceptibility to cancer. However, pathway dynamics are often studied in cell lines as alternative to primary cells, disregarding variability. To compare DDR dynamics in the cell line HepG2 with primary human hepatocytes (PHHs), we developed a HepG2-based computational model that describes the dynamics of DDR regulator p53 and targets MDM2, p21 and BTG2. We used this model to generate simulations of virtual PHHs and compared the results to those for PHH donor samples. Correlations between baseline p53 and p21 or BTG2 mRNA expression in the absence and presence of DNA damage for HepG2-derived virtual samples matched the moderately positive correlations observed for 50 PHH donor samples, but not the negative correlations between p53 and its inhibitor MDM2. Model parameter manipulation that affected p53 or MDM2 dynamics was not sufficient to accurately explain the negative correlation between these genes. Thus, extrapolation from HepG2 to PHH can be done for some DDR elements, yet our analysis also reveals a knowledge gap within p53 pathway regulation, which makes such extrapolation inaccurate for the regulator MDM2. This illustrates the relevance of studying pathway dynamics in addition to gene expression comparisons to allow reliable translation of cellular responses from cell lines to primary cells. Overall, with our approach we show that dynamical modeling can be used to improve our understanding of the sources of interindividual variability of pathway dynamics.

Pressure Overload Activates DNA-Damage Response in Cardiac Stromal Cells: A Novel Mechanism Behind Heart Failure With Preserved Ejection Fraction?

Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome characterized by impaired left ventricular (LV) diastolic function, with normal LV ejection fraction. Aortic valve stenosis can cause an HFpEF-like syndrome by inducing sustained pressure overload (PO) and cardiac remodeling, as cardiomyocyte (CM) hypertrophy and fibrotic matrix deposition. Recently, in vivo studies linked PO maladaptive myocardial changes and DNA damage response (DDR) activation: DDR-persistent activation contributes to mouse CM hypertrophy and inflammation, promoting tissue remodeling, and HF. Despite the wide acknowledgment of the pivotal role of the stromal compartment in the fibrotic response to PO, the possible effects of DDR-persistent activation in cardiac stromal cell (C-MSC) are still unknown. Finally, this novel mechanism was not verified in human samples. This study aims to unravel the effects of PO-induced DDR on human C-MSC phenotypes. Human LV septum samples collected from severe aortic stenosis with HFpEF-like syndrome patients undergoing aortic valve surgery and healthy controls (HCs) were used both for histological tissue analyses and C-MSC isolation. PO-induced mechanical stimuli were simulated in vitro by cyclic unidirectional stretch. Interestingly, HFpEF tissue samples revealed DNA damage both in CM and C-MSC. DDR-activation markers γH2AX, pCHK1, and pCHK2 were expressed at higher levels in HFpEF total tissue than in HC. Primary C-MSC isolated from HFpEF and HC subjects and expanded in vitro confirmed the increased γH2AX and phosphorylated checkpoint protein expression, suggesting a persistent DDR response, in parallel with a higher expression of pro-fibrotic and pro-inflammatory factors respect to HC cells, hinting to a DDR-driven remodeling of HFpEF C-MSC. Pressure overload was simulated in vitro, and persistent activation of the CHK1 axis was induced in response to in vitro mechanical stretching, which also increased C-MSC secreted pro-inflammatory and pro-fibrotic molecules. Finally, fibrosis markers were reverted by the treatment with a CHK1/ATR pathway inhibitor, confirming a cause-effect relationship. In conclusion we demonstrated that, in severe aortic stenosis with HFpEF-like syndrome patients, PO induces DDR-persistent activation not only in CM but also in C-MSC. In C-MSC, DDR activation leads to inflammation and fibrosis, which can be prevented by specific DDR targeting.

Resistance to DNA repair inhibitors in cancer.

The DNA damage response (DDR) represents a complex network of proteins which detect and repair DNA damage, thereby maintaining the integrity of the genome and preventing the transmission of mutations and rearranged chromosomes to daughter cells. Faults in the DDR are a known driver and hallmark of cancer. Furthermore, inhibition of DDR enzymes can be used to treat the disease. This is exemplified by PARP inhibitors (PARPi) used to treat cancers with defects in the homologous recombination DDR pathway. A series of novel DDR targets are now also under pre-clinical or clinical investigation, including inhibitors of ATR kinase, WRN helicase or the DNA polymerase/helicase Polθ (Pol-Theta). Drug resistance is a common phenomenon that impairs the overall effectiveness of cancer treatments and there is already some understanding of how resistance to PARPi occurs. Here, we discuss how an understanding of PARPi resistance could inform how resistance to new drugs targeting the DDR emerges. We also discuss potential strategies that could limit the impact of these therapy resistance mechanisms in cancer.

Targeting DNA damage response in cardiovascular diseases: from pathophysiology to therapeutic implications.

Cardiovascular diseases (CVDs) arise from a complex interplay among genomic, proteomic, and metabolomic abnormalities. Emerging evidence has recently consolidated the presence of robust DNA damage in a variety of cardiovascular disorders. DNA damage triggers a series of cellular responses termed DNA damage response (DDR) including detection of DNA lesions, cell cycle arrest, DNA repair, cellular senescence, and apoptosis, in all organ systems including hearts and vasculature. Although transient DDR in response to temporary DNA damage can be beneficial for cardiovascular function, persistent activation of DDR promotes the onset and development of CVDs. Moreover, therapeutic interventions that target DNA damage and DDR have the potential to attenuate cardiovascular dysfunction and improve disease outcome. In this review, we will discuss molecular mechanisms of DNA damage and repair in the onset and development of CVDs, and explore how DDR in specific cardiac cell types contributes to CVDs. Moreover, we will highlight the latest advances regarding the potential therapeutic strategies targeting DNA damage signalling in CVDs.

Targeting the Homologous Recombination Pathway in Cancer With a Novel Class of RAD51 Inhibitors.

Targeting DNA damage response (DDR) pathway has been proposed as an approach for amplifying tumor-specific replicative lesions. RAD51 plays a central role in the DDR process, and thus represents a promising anti-tumor target. We here report the discovery of a series of next generation RAD51 inhibitors that can prevent RAD51 foci formation. The lead compounds dramatically impaired human cancer cell growth, induced cell cycle arrest in S-phase, and resulted in elevated γH2AX. Furthermore, cancer cells became sensitized to chemotherapy and other DDR inhibitors. Dosed either as a single agent or in combination with cisplatin, the compounds significantly inhibited tumor growth in vivo. By upregulating ATR-CHK1 signaling, the RAD51 inhibitors increased surface PD-L1 levels in various tumor cells, suggesting a potential combination of RAD51 inhibitors with PD-1/PD-L1 blockade. Overall, our findings provide the preclinical rationale to explore RAD51 inhibitors as monotherapy or in combination with chemotherapy, immunotherapy or DDR-targeting therapy in cancer treatment.

Transcriptomic Profiling of DNA Damage Response in Patient-Derived Glioblastoma Cells before and after Radiation and Temozolomide Treatment

Glioblastoma is a highly aggressive, invasive and treatment-resistant tumour. The DNA damage response (DDR) provides tumour cells with enhanced ability to activate cell cycle arrest and repair treatment-induced DNA damage. We studied the expression of DDR, its relationship with standard treatment response and patient survival, and its activation after treatment. The transcriptomic profile of DDR pathways was characterised within a cohort of isocitrate dehydrogenase (IDH) wild-type glioblastoma from The Cancer Genome Atlas (TCGA) and 12 patient-derived glioblastoma cell lines. The relationship between DDR expression and patient survival and cell line response to temozolomide (TMZ) or radiation therapy (RT) was assessed. Finally, the expression of 84 DDR genes was examined in glioblastoma cells treated with TMZ and/or RT. Although distinct DDR cluster groups were apparent in the TCGA cohort and cell lines, no significant differences in OS and treatment response were observed. At the gene level, the high expression of ATP23, RAD51C and RPA3 independently associated with poor prognosis in glioblastoma patients. Finally, we observed a substantial upregulation of DDR genes after treatment with TMZ and/or RT, particularly in RT-treated glioblastoma cells, peaking within 24 h after treatment. Our results confirm the potential influence of DDR genes in patient outcome. The observation of DDR genes in response to TMZ and RT gives insight into the global response of DDR pathways after adjuvant treatment in glioblastoma, which may have utility in determining DDR targets for inhibition.

Targeting DNA Damage Response and Immune Checkpoint for Anticancer Therapy.

Deficiency in DNA damage response (DDR) genes leads to impaired DNA repair functions that will induce genomic instability and facilitate cancer development. However, alterations of DDR genes can serve as biomarkers for the selection of suitable patients to receive specific therapeutics, such as immune checkpoint blockade (ICB) therapy. In addition, certain altered DDR genes can be ideal therapeutic targets through adapting the mechanism of synthetic lethality. Recent studies indicate that targeting DDR can improve cancer immunotherapy by modulating the immune response mediated by cGAS-STING-interferon signaling. Investigations of the interplay of DDR-targeting and ICB therapies provide more effective treatment options for cancer patients. This review introduces the mechanisms of DDR and discusses their crucial roles in cancer therapy based on the concepts of synthetic lethality and ICB. The contemporary clinical trials of DDR-targeting and ICB therapies in breast, colorectal, and pancreatic cancers are included.

Micropeptide PACMP inhibition elicits synthetic lethal effects by decreasing CtIP and poly(ADP-ribosyl)ation

Synthetic lethality through combinatorial targeting DNA damage response (DDR) pathways provides exciting anticancer therapeutic benefit. Currently, the long noncoding RNAs (lncRNAs) have been implicated in tumor drug resistance; however, their potential significance in DDR is still largely unknown. Here, we report that a human lncRNA, CTD-2256P15.2, encodes a micropeptide, named PAR-amplifying and CtIP-maintaining micropeptide (PACMP), with a dual function to maintain CtIP abundance and promote poly(ADP-ribosyl)ation. PACMP not only prevents CtIP from ubiquitination through inhibiting the CtIP-KLHL15 association but also directly binds DNA damage-induced poly(ADP-ribose) chains to enhance PARP1-dependent poly(ADP-ribosyl)ation. Targeting PACMP alone inhibits tumor growth by causing a synthetic lethal interaction between CtIP and PARP inhibitions and confers sensitivity to PARP/ATR/CDK4/6 inhibitors, ionizing radiation, epirubicin, and camptothecin. Our findings reveal that a lncRNA-derived micropeptide regulates cancer progression and drug resistance by modulating DDR, whose inhibition could be employed to augment the existing anticancer therapeutic strategies.

DNA-Damage-Response-Targeting Mitochondria-Activated Multifunctional Prodrug Strategy for Self-Defensive Tumor Therapy.

We report a novel multifunctional construct, M1, designed explicitly to target the DNA damage response in cancer cells. M1 contains both a floxuridine (FUDR) and protein phosphatase 2A (PP2A) inhibitor combined with a GSH-sensitive linker. Further conjugation of the triphenylphosphonium moiety allows M1 to undergo specific activation in the mitochondria, where mitochondria-mediated apoptosis is observed. Moreover, M1 has enormous effects on genomic DNA ascribed to FUDR's primary function of impeding DNA/RNA synthesis combined with diminishing PP2A-activated DNA repair pathways. Importantly, mechanistic studies highlight the PP2A obtrusion in FUDR/5-fluorouracil (5-FU) therapy and underscore the importance of its inhibition to harbor therapeutic potential. HCT116 cell xenograft-bearing mice that have a low response rate to 5-FU show a prominent effect with M1, emphasizing the importance of DNA damage response targeting strategies using tumor-specific microenvironment-activatable systems.