Disulfidptosis-a regulated cell death caused by disulfide stress under glucose starvation and high SLC7A11-offers a potential cancer vulnerability, but its regulatory landscape and therapeutic tractability remain unclear. We sought to (i) map disulfidptosis susceptibility across cancers, (ii) define associated pathways and regulators, and (iii) test whether targeting these pathways enhances disulfidptosis to improve antitumor efficacy. Methods: We curated 43 core regulators to compute the disulfidptosis score (D-score) across ~10,000 TCGA tumors, benchmarked with glucose-starvation datasets. Correlation screening yielded 506 candidate regulators, integrated into a refined score (D-score+). We associated D-score+ with hallmark pathways, genomic instability and DNA-repair signatures. Experimental validation used glucose-deprivation models, non-reducing immunoblotting and immunofluorescence of cytoskeletal proteins, CRISPR perturbations, and pharmacologic combinations with cell-cycle arrest agents and PARP inhibitors. Public clinical and drug-response cohorts supported translational analyses. Results: D-score tracked experimental triggers (glucose starvation) and revealed cancer-type-specific prognostic patterns. D-score+ positively correlated with cell-cycle programs (e.g., G2/M checkpoint, spindle) and negatively with DNA-repair activity, while aligning with multiple genomic-instability signatures. Beyond F-actin, tubulin exhibited disulfide-dependent mobility shifts and microtubule disassembly. Combining disulfidptosis with cell-cycle arrest drugs synergistically increased cell death across models, with dose-responsive effects and cross-cancer activity. PARP inhibition synergized with disulfidptosis in multiple lines, and higher susceptibility tracked with PARP-inhibitor sensitivity datasets; CRISPR loss of ATM or FANCD2 further sensitized cells. D-score+ was lower in metastatic versus primary tumors and inversely related to EMT in select cancers; glucose starvation impaired migration in wound-healing assays. Conclusions: Inducing cell-cycle arrest and compromising DNA repair enhances cancer susceptibility to disulfidptosis, in part via redox-dependent disruption of actin and microtubules. D-score/D-score+ provide quantitative biomarkers to stratify tumors for combination strategies pairing disulfidptosis induction with cell-cycle inhibitors or PARP inhibitors. These findings nominate disulfidptosis-related pathways as actionable targets and support integrating disulfidptosis profiling into precision oncology, warranting in vivo and clinical validation.

2025-10-01·MOLECULAR CELL

PARP1 auto-modification promotes faithful Okazaki fragment processing and limits replication fork speed

Article

作者: Elsborg, Jonas D ; Smith, Rebecca ; Adelantado-Rubio, Alba ; Zentout, Siham ; Duxin, Julien P ; Nielsen, Michael L ; Hendriks, Ivo A ; Maya-Mendoza, Apolinar ; Fábian, Zita ; Bartek, Jiri ; Buch-Larsen, Sara C ; Pék, Ramóna ; Huet, Sébastien ; Imburchia, Victor ; Munk, Sebastian H N

Poly(ADP-ribose) polymerase (PARP) inhibitors have proven their efficacy for treating tumors defective in homologous recombination via synthetic lethality. In response to DNA breaks, PARP1 is the primary ADP-ribosylation writer, modifying itself (auto-modification) and other proteins to facilitate repair. However, enzymatic inhibition blocks both processes, making it difficult to dissect their distinct functional roles. Using proteomics and site-directed mutagenesis, we identified a PARP1 mutant deficient in auto-modification, yet it retains catalytic activity. This separation-of-function mutant revealed that PARP1 auto-modification slows DNA replication fork progression but is dispensable for repair factor recruitment. Instead, auto-modification promotes the timely release of PARP1 at DNA break sites and prevents the formation of replication stress. Simultaneous inhibition of FEN1 and loss of PARP1 auto-modification gives rise to synthetic lethality, implicating auto-modification in Okazaki fragment processing. Our results demonstrate that trapping of PARP at DNA breaks impedes repair factor accessibility, constituting an important dimension of PARP-inhibitor-driven cytotoxicity.

2024-12-01·GYNECOLOGIC ONCOLOGY

ATR inhibition increases reliance on PARP-mediated DNA repair revealing an improved therapeutic strategy for cervical cancer

Article

作者: Benbrook, Doris M. ; Elayapillai, Sugantha Priya ; Parker, Madison ; Hannafon, Bethany N ; Hannafon, Bethany N. ; Kennedy, Amy ; Moxley, Katherine M ; Lausen, James ; Moxley, Katherine M. ; Dogra, Samrita ; Benbrook, Doris M

OBJECTIVE:

Cervical cancer results from persistent infection with high-risk human papillomavirus (HR-HPV) and the expression of E6 and E7 oncoproteins. E6 and E7 compromise the activity of p53 and Rb, the G1-S cell cycle checkpoint, and ATM-mediated DNA damage repair (DDR), which in turn increases reliance on ATR- and PARP-mediated DDR at the G2 cell cycle checkpoint. This study aimed to determine the effects of an ATR inhibitor (ATRi, AZD6738) and a PARP-inhibitor (PARPi, AZD2281) on HR-HPV+ cervical cancer cell lines.

METHODS:

The effects of ATRi and PARPi, alone and in combination, on metabolic viability, cell cycle arrest, apoptosis, and DDR pathways in cervical cancer cell lines were evaluated in vitro, and the in vivo tumor response was evaluated using a xenograft model.

RESULTS:

Cervical cancer cells were sensitive to ATRi and PARPi monotherapy. The combination therapy was only synergistic in reducing metabolic viability when exposed to ATRi first, followed by PARPi, owing to ATRi-mediated upregulation of PARP expression. Combination of ATRi and PARPi induced G2 cell cycle arrest and apoptosis. PARPi induced DNA damage and γH2AX phosphorylation, which was further increased by ATRi treatment. However, PARPi-induced Rad51 foci formation was reduced by ATRi treatment, suggesting the inhibition of homologous recombination repair. ATRi significantly reduced cervical cancer xenograft tumor growth and was not affected by simultaneous PARPi treatment at the doses studied.

CONCLUSIONS:

Our findings show that ATRi increased reliance on PARP for metabolic viability, the combination of ATRi and PARPi induced synthetic lethality in cervical cancer in vitro, and reduced tumor burden in vivo.

项与 PARP inhibitor(Satyarx Pharma) 相关的新闻（医药）

2022-08-02

·Endpts

After FDA requests a new trial, Allarity drops a cancer drug from solo development

The US-Danish biotech Allarity Therapeutics is having to pivot its pipeline strategy after the FDA forced them to go back to the drawing board for an oncology therapy. Allarity announced on Tuesday that the board has mandated the biotech to refocus its oncology strategy away from the development of monotherapies and toward the development of “more promising and clinically relevant combination therapies.” The move also comes after the FDA had an advisory meeting over the Phase III development for dovitinib — a former Novartis candidate , as a therapy for metastatic renal cell carcinoma (mRCC). The FDA indicated the company would need to conduct a new dosing study before any Phase III can move forward. However, conducting a new dosing study would cause further delays and drive up the cost and time of production so the company has chosen to drop it instead. While Allarity determined that advancing dovitinib is no longer commercially viable, the drug will continue to be externally developed as a potential monotherapy for pediatric cancers. With its switch to combinations, the board said this can potentially increase the company’s ability to attract additional funding from life science investors, as well as broaden the potential for future partnerships with larger pharmaceutical companies. But Allarity will also be facing stiff competition in the combination therapies field. Several major pharmas have been racing to get combination therapies out to the public. For Allarity’s new pipeline, it will start enrollment for Phase Ib/II of a PARP inhibitor with dovitinib, for the treatment of metastatic ovarian cancer by the end of the year. It is not shying away from the mRCC space, as the biotech is also evaluating other potential studies for either stenoparib or dovitinib combined with another oncology therapeutic for its treatment. Allarity’s ongoing Phase II studies of stenoparib, for ovarian cancer on its own, and Ixempra for metastatic breast cancer, will continue through their data readouts. “I am confident that our strategic shift of focus and resources is the correct path forward for Allarity given the current regulatory and market realities and will best leverage our DRP companion diagnostics to match the right patients to cancer therapeutic from which they will most likely benefit,” said Allarity’s interim CEO James Cullem. The move needs to have a positive effect on investors as the company is sitting just above penny stock status and its stock price $ALLR has fallen 89% since December 2021.

2022-06-06

·新浪医药新闻

2022 ASCO：RAD51靶点研究数据更新国内知名药企已布局研究进展如何？

文 | 药疯每年的ASCO大会，都会得到肿瘤领域相关研究人员的重点关注。哪些靶点显示成药潜力？哪些候选药物获得积极数据？哪些癌种得到有效控制？所有的一切都在触动着肿瘤药物研究人员和投资商的敏感神经。尤其是那些持续亮相大会的潜力品种、优势品种，受关注度自然更高。靶点RAD51，凭借其所具备的研发潜力和相应品种的初战告捷，连续多年亮相ASCO大会，基于对该靶点的持续跟踪，总结前期研究+当前进展的基础上，汇总信息，以形成对一个靶点研究进展的总体概况。 01 RAD51/靶点背景介绍 RAD51基因，定位于第15号染色体，含有9个外显子和8个内含子，编码一条由339个氨基酸组成的多肽；RAD51首次被报道的时间为1993年，由ogawaH等人克隆，是真核生物体内的一种DNA重组酶。图1.1 RAD51存在的两种二聚体形态 RAD51同系物有XRCC2、XRCC3、RAD51B（RAD51L1）、RAD51C（RAD51L2）和RAD51D（RAD51L3），这些同系物与RAD51有20%～30%的氨基酸序列相似度，且与RAD51共同参与HR修复过程。图1.2 人类RAD51类似物组成的复合物 DSBs发生时，断裂末端处在MRE11/RAD50/NBS1(MRN)三元复合物中的MRE11的作用下，沿着5'向3'方向切割，暴露了与复制蛋白A(RPA)分子结合的3'单链DNA末端。RAD51竞争性置换RPA并与单链DNA的3'末端上结合，形成连续的RAD51-单链DNA复合物；后RAD51识别同源DNA模板，催化DNA链的配对、延伸；最后在核酸酶和连接酶的作用下，形成完整的双链DNA分子。图1.3 RAD51催化的同源重组修复 02 全球在研药物品种汇总针对于RAD51这个靶点，全球进展最快的品种为Cyteir公司开发的抑制剂CYT-0851，该品种为口服药物，旨在通过抑制RAD51介导的HR修复；此外，Cyteir还布局了后续品种CYT-1853，但据官网介绍，尚未进入临床。PS：CYT-0851尚未进入中国进行临床。图2.1 CYT-0851重要临床相关内容此外，早期文献报道的品种还有Halenaquinone、B02、RI-1、IBR2等，但由于毒性大等副作用问题，均为进入到临床阶段。另，在RAD51领域进行研发投入的公司主要还有SATYA Pharma Innovations（品种代号SAT-93和SAT-13），而国内布局RAD51的公司主要为先声药业（品种代号SCR-6992）。据先声药业官网介绍：先声药业自主研发的临床前候选分子SCR-6992作为新一代RAD51抑制剂，在体外对人淋巴瘤Daudi细胞具有显着的特异性抗增殖能力(IC50=12 nM)，与化疗药物或DDR靶向药物联合应用时，在淋巴瘤和实体瘤细胞系中产生协同抗癌反应。动物实验证实，SCR-6992显著抑制恶性淋巴瘤肿瘤Daudi的肿瘤生长，当以80mg/kg/天口服给药时观察到肿瘤消退。SCR-6992还在啮齿动物和犬类动物模型中显示良好的药代动力学特征。在14天剂量耐受研究中，当剂量分别高达200 mg/kg和40 mg/kg时，无明显的血液学或胃肠道毒性。 03 2022 ASCO关于CYT-0851的报道对于RAD51的报道，还是要关注重点品种CYT-0851的动向；令人欣慰的是，继2021年亮相ASCO后，本年度该品种继续亮相ASCO，仅凭此即可以看到很多积极内容。图3.1 2021-2022/CYT-0851连续2年登陆ASCO （图片源：https://conferences.asco.org/am/attend） 2022年，关于CYT-0851的题目为“Phase 1 results of a phase 1/2 trial of CYT-0851, a first-in-class inhibitor of RAD51-mediated homologous recombination, in patients with advanced solid and hematologic cancers”，临床试验资料为NCT03997968，具体内容如下：按照3+3设计，晚期血液肿瘤和实体肿瘤患者接受连续28天/周期的剂量递增的CYT-0851治疗；主要目标是确定最大耐受剂量；次要目标包括安全性、药代动力学特征和抗肿瘤活性。结果：截至2021年11月15日，73名晚期癌症患者（非霍奇金淋巴瘤 n = 18；肉瘤 n = 16；胰腺癌 n = 11；乳腺癌 n = 8；头颈部鳞状细胞癌 n = 6；卵巢癌 n = 4；小细胞肺癌 n = 4；其他 n = 4；骨髓瘤 n = 2）在12个队列中接受治疗（每日总剂量：30 mg 至1200 mg）。一名患者在1200 mg时出现可逆性代谢性酸中毒的剂量限制性毒性(DLT)。3名患者中有2名（给药800mg），在第二周期治疗中出现了可逆的DLT样事件~Gr3干性皮肤、Gr3肌痛和多发性关节炎。10名患者中有3名（给药600mg），在第一周期中出现了DLT事件~1名患者出现Gr3厌食症、Gr3口腔炎、呕吐和脱水的SAE，2名患者出现Gr3疲劳。每天给药400 mg无DLT发生，设定为RP2D。进一步统计，42名患者(57.5%)发生了CYT-0851相关的不良反应，其中12名(16.4%)发生了Gr3/4 AE。无与治疗相关死亡事件发生。2名患者（2.7%，给药600mg/800mg）因AE退出试验。最常见因CYT-0851相关AE主要是包括疲劳(20.5%)、高尿酸血症(11%)、恶心(11%)、脱发(9.6%)、便秘(8.2%)和头痛(8.2%)。CYT-0851，半衰期为3天。每天400 mg的暴露量与临床前模型中的趋势一致，呈剂量相关。综上，研究者认为，CYT-0851在I期晚期癌症患者群体中显示出确切且具有广泛的临床疗效。安全性数据是具有正向指导意义的，AE可逆。六个扩展队列（DLBCL、滤泡性淋巴瘤、骨髓瘤、胰腺癌、卵巢癌和肉瘤）正在进行注册以推进RP2D。该品种与其他化疗药的临床I期试验也在进行当中。PS：由上可推断化疗药物为吉西他滨、卡培他滨、苯达莫司汀，等。图3.2 NCT03997968主要临床目标（图片源：https://clinicaltrials.gov/ct2/home） 04 其他RAD51亮相2022 ASCO的报告除上述RAD51重点药物CYT-0851外，RAD51这个靶点还多次出现在其他报告当中，由此足见该靶点的重要程度和热度；相关报告具体如下所示： 1 Comprehensive whole-exome and transcriptome profiling to identify actionable alterations associated with response to PARP inhibitors in breast cancer. 2 DOLAF: An international multicenter phase II trial of durvalumab (MEDI4736) plus olaparib plus fulvestrant in patients with metastatic or locally advanced ER-positive, HER2-negative breast cancer selected using criteria that predict sensitivity to olaparib. 3 Detection of homologous recombination deficiency (HRD) in cell-free DNA (cfDNA) using an amplicon-based next-generation sequencing (NGS) assay. 4 Circulating tumor DNA (ctDNA) determinants of improved outcomes in patients (pts) with advanced solid tumors receiving the ataxia telangiectasia and Rad3-related inhibitor (ATRi), RP-3500, in the phase 1/2a TRESR trial (NCT04497116). 5 Adaptive response analysis of colorectal cancer cells to low-dose oxaliplatin as a tool to deciphering mechanisms of synergistic drug interaction. 6 Identification of homologous recombination deficiency (HRD) by RAD51 in a tumor molecular profiling program for precision medicine. 7 The impact of HRD in patients with pancreatic adenocarcinoma undergoing surgical resection: An updated analysis. 8 Potential indicators in circulating cell-free DNA for monitoring PARP inhibitor resistance in high-grade serous ovarian cancer. 9 Efficacy of maintenance olaparib plus bevacizumab in patients with newly diagnosed advanced ovarian cancer according to BRCA mutation genotype in the phase III PAOLA-1/ENGOT-ov25 trial. 10 Landscape of homologous recombination reversion mutations in gynecologic malignancies. 11 Impact of cancer susceptibility gene (CSG) mutations in advanced NSCLC (aNSCLC). 12 Rates of pathogenic variants in common cancer genes among different racial/ ethnic groups. 13 Ancestry-specific risk of triple-negative breast cancer (TNBC) associated with germline pathogenic variants (PV) in hereditary cancer (CA) predisposition genes. 14 Heart toxicity effects (HTE) of anthracyclines-containing regimens (ACRs) in patients with breast cancer (BC) carrying mutational signature of homologous recombination deficiency (HRD). 15 Retrospective analysis of non-BRCA gene pathogenicity variation in Chinese patients with ovarian cancer. 16 Genetic epidemiology of breast cancer (BC) risk genes from a diverse realworld oncology practice in Brazil. 17 Correlative results from NCI protocol 10250: A phase II study of temozolomide and olaparib for the treatment of advanced uterine leiomyosarcoma. 通过研究表格中的信息及具体的报告内容，总结如下：从癌种来说，与RAD51相关领域主要集中于肿瘤中的乳腺癌（包括TNBC）、结直肠癌、胰腺癌、卵巢癌，等；基因主要相关BRCA突变基因，等；药物主要相关PARP抑制剂（如奥拉帕利）、ATR抑制剂、化疗药物（如奥沙利铂），等。报告中相关于RAD51的靶点内容，主要是体现在肿瘤发生时RAD51相关的融合和高表达。且其出现频次和地位几乎等同于合成致死及相关重点靶标如ATM、ATR、CHEK1、CHEK2、WEE1等，属于癌症易感基因。 05 2022年国内在RAD51方面的文献研究通过对国内的文献进行搜索，对于RAD51这个靶点，也有一些研究进展，尤其是与靶点相关，以及肿瘤转移和耐药。 ➣ RAD51促进恶性肿瘤转移和耐药 RAD51在恶性肿瘤中的高表达已经得到了广泛证实，癌症基因组图谱（TCGA）数据库显示，在926个病例中占比较高的肿瘤类别包括卵巢癌、乳腺癌和支气管或肺癌。有研究表明，通过生物信息学分析证明卵巢癌中RAD51表达高于正常卵巢，且这种高表达与癌症的DNA损伤修复增强、对多类化学药物的耐药性和较短的总生存期（OS）显著相关，证实了RAD51可以作为卵巢癌相关的生物标志物。还有研究发现，顺铂可以增强RAD51的表达，其高表达会导致小鼠对顺铂的耐药；而二甲双胍通过降低RAD51蛋白稳定性并增加其泛素化调节RAD51的表达，逆转肿瘤耐药。 ➣ 与PARP、BRCA相关的研究 PARP抑制剂，凭借合成致死概念的验证成功，成为了合成致死方向的领头羊，并成功开发了一系列上市药物。PARP抑制剂对于具有乳腺癌易感(BRCA)基因缺陷的卵巢癌患者有很好的治疗效果。随着研究的深入，人们发现PARP抑制剂对于很多没有BRCA基因缺陷的患者也非常有效。BRCA1和BRCA2是经典的抑癌基因，在DNA双链断裂同源重组修复中起举足轻重的作用。有研究显示，BRCA2和RAD51基因突变可以促进卵巢癌的发生发展。且证实BRCA1、BRCA2、RAD51和FANCD2蛋白在多种癌症中过表达，而且这些蛋白的过表达有可能是患者不良预后的指标。 06 结论综上，即为RAD51的在研概况。进一步总结如下：1）靶点机制清晰，活性特点正在逐渐被证实；2）药物开发进展相对积极；3）跟进企业不多，赛道尚不拥挤；4）合成致死领域，未来可期。参考资料（往下滑动查看更多）： 1.2021年度ASCO值得深入关注的在研靶标. 新浪医药 2.Crystal structure of a Rad51 filament. nature structural&molecularbiology. 3.Felix Blanc-Durand et. Al EFFORT: Evaluation of a RAD51 functional assay in advanced ovarian cancer, a GINECO/GINEGEPS study.2021 ASCO, abs 5513. 4.RAD51 paralog function in replicative DNA damage and tolerance. https://doi.org/10.1016/j.gde.2021.06.010 5.https://conferences.asco.org/am/attend 6.https://www.clinicaltrials.gov/ct2/show/NCT03997968?term=cyteir&draw=2&rank=1 7.RAD51在恶性肿瘤转移和耐药中的作用及研究进展.CNKI 8.BRCA1、BRCA2、RAD51和FANCD2在上皮性卵巢癌中的表达及其与临床病理特征的关系.CNKI 9.http://www.simcere.com/news/detail.aspx?mtt=216 10.2022-ASCO-Annual-Meeting-Abstract

ASCO会议免疫疗法

100 项与 PARP inhibitor(Satyarx Pharma) 相关的药物交易

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