ATR Inhibitors in Platinum-Resistant Ovarian Cancer

Li, Siyu; Wang, Tao; Fei, Xichang; Zhang, Mingjun

doi:10.3390/cancers14235902

Cited by 8 publications

(7 citation statements)

References 147 publications

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“…In this study, we observed that the expression of DDUP was strongly associated with CDDP resistance in ovarian cancer and was inversely correlated with the survival rate of patients with ovarian cancer receiving platinum-based chemotherapy. Notably, treatment with an ATR inhibitor abolished DDUP-induced DNA damage repair and protection against apoptosis, leading to the development of CDDP-resistant ovarian cancer cells that were more vulnerable to platinum-based chemotherapeutic agents [ 39 , 40 ]. Altogether, the findings highlight the importance of DDUP as a predictive biomarker of CDDP resistance and possibly represent a potential strategy for the treatment of CDDP-resistant ovarian cancer.…”

Section: Discussionmentioning

confidence: 99%

The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer

Ren,

Qing,

Wei

et al. 2023

Cell Death Dis

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Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer

Ren,

Qing,

Wei

et al. 2023

Cell Death Dis

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“…An increased sensitivity to ATRi in HR-deficient cancers in ovarian cancer cell lines has been shown in literature (Krajewska et al, 2015), however, the specific pathway information was not known and could be used to identify biomarkers for patient selection. Next, we compared the resistance mechanism of ATRi to irinotecan and gemcitabine in ovarian cancer to identify potential similarities or differences to these compounds, with irinotecan suggested and gemcitabine being tested as combination therapy with ATRi in platinum-resistant ovarian cancer (Konstantinopoulos et al, 2023;Li et al, 2022). Our results showed a different profile of genes driving resistance to AZD6738 compared to irinotecan in ovarian cancer (Figure 11), whereas its resistance mechanism was similar to that observed in gemcitabine (involving predominantly G1/S cell cycle genes that drive cell cycle progression through E2F transcription and to a lesser extent NER genes).…”

Section: Signaling Pathway Evaluation Of Atr Inhibitors Such As Azd6738mentioning

confidence: 99%

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

Truter,

Bergh,

van den Heever

et al. 2024

Preprint

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Introduction: There are many cancer drugs in development which target the DNA damage response (DDR), following early successes of drugs such as olaparib. However, various challenges to the success of these inhibitors exist, including the emergence of resistance, the identification of appropriate biomarkers to identify patients who will respond to treatment, as well as the identification of combination therapies that improve efficacy without a concomitant increase in toxicity. While the identification of biomarkers of resistance could aid in overcoming these challenges, current methods mostly generate lists of potential genes, proteins that display changes in cancer patients, without exposing the underlying, and often critical, mechanisms of resistance. Methods: We have developed the Adaptable Large-Scale Causal Analysis (ALaSCA) software platform, which applies Pearlian Causal Inference (PCI) techniques to specifically transcriptomic, proteomic and phenotypic multi-omics data. ALaSCA quantifies the causal contributions of different biological pathways to an outcome such as responsiveness to treatment. The strength of applying PCI to biological pathways lies in quantifying the causal contributions of targets, through their related pathways, to drug sensitivity - as opposed to merely enriching or grouping lists of genes into pathways. We applied ALaSCA to transcriptomic data for several different compounds related to three known inhibitor types that target DDR proteins: an ATR, a CDK7, and several PARP inhibitors. Our aim was to use causal methods to evaluate biological signaling pathways to identify resistance mechanisms that can be used for patient stratification and development of combination therapies in breast, ovarian and non-small cell lung cancer (NSCLC). Key findings: We observed that niraparib seems to have a different resistance mechanism than other PARP inhibitors in breast and NSCLC, which is driven by CDK1 as opposed to base excision or nucleotide excision repair. Additionally, CDK7 appears to be a significant driver of PARP inhibitor resistance, especially for niraparib, through predominantly the G2/M cell cycle phase and to a lesser extent nucleotide excision repair in breast and ovarian cancer, but not in NSCLC. Lastly, we identified that genes from the homologous recombination pathway drive resistance to AZD6738, an ATR inhibitor, in breast cancer, and that AZD6738 and irinotecan have differing resistance mechanisms in ovarian cancer, indicating the potential of combining these treatments. Next steps: Our findings demonstrate the potential of ALaSCA to generate interesting insights for treatments when applied to public data and well-known inhibitors. Partnership with industry drug discovery groups using proprietary data to rerun the above evaluations will further refine and confirm these findings.

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“…The ATR/CHK1 pathway acts as a sensor detecting single-stranded DNA breaks that lead to cell-cycle arrest. Combined ATR and PARP inhibition has been evaluated across multiple studies; despite promising preclinical data, the phase 2 CAPIRI trial failed to demonstrate a clinical benefit in platinum-resistant epithelial ovarian cancer [ 129 , 130 ]. Prexasertib, a CHK1 inhibitor, was also evaluated in BRCA wild-type HGSOC, where the majority (79%) of the patients had platinum-resistant or refractory disease.…”

Section: Overcoming Platinum Resistance In Ovarian Cancermentioning

confidence: 99%

Ovarian Cancer—Insights into Platinum Resistance and Overcoming It

et al. 2023

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Ovarian cancer is the most lethal gynecologic malignancy. Platinum-based chemotherapy is the backbone of treatment for ovarian cancer, and although the majority of patients initially have a platinum-sensitive disease, through multiple recurrences, they will acquire resistance. Platinum-resistant recurrent ovarian cancer has a poor prognosis and few treatment options with limited efficacy. Resistance to platinum compounds is a complex process involving multiple mechanisms pertaining not only to the tumoral cell but also to the tumoral microenvironment. In this review, we discuss the molecular mechanism involved in ovarian cancer cells’ resistance to platinum-based chemotherapy, focusing on the alteration of drug influx and efflux pathways, DNA repair, the dysregulation of epigenetic modulation, and the involvement of the tumoral microenvironment in the acquisition of the platinum-resistant phenotype. Furthermore, we review promising alternative treatment approaches that may improve these patients’ poor prognosis, discussing current strategies, novel combinations, and therapeutic agents.

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ATR Inhibitors in Platinum-Resistant Ovarian Cancer

Cited by 8 publications

References 147 publications

The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer

The DDUP protein encoded by the DNA damage-induced CTBP1-DT lncRNA confers cisplatin resistance in ovarian cancer

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

Ovarian Cancer—Insights into Platinum Resistance and Overcoming It

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