延缓parp抑制剂的耐药
PARP抑制剂包括奥拉帕尼、尼拉帕尼、他拉唑帕尼、氟唑帕利等药物；HRD检测评分高皆可以用parp抑制剂。延缓parp抑制剂首先要同时控制副作用：parp抑制剂的骨髓抑制副作用非常严重，自救群已经有四五位实体瘤病友用parp抑制剂后又得了白血病。用papr抑制剂要同时用补髓生血方、参芪补肺汤等补髓生血、抑制炎症的中药方防治副作用。
用parp抑制剂可以遵循用靶向药的一般原则“IC50值越用越小”，序贯用parp抑制剂。
也可联用其他相关通路的药物，抑制旁路激活，从而延缓parp抑制剂的耐药：
1、Dapagliflozin 达格列净抑制 CDK1、 PBK 、CHEK1，从而延缓PARP抑制剂耐药；Bosutinib 伯舒替尼抑制CHK1、 WEE1、SRC、PI3K/AKT/mTOR、MAPK/ERK和JAK/STAT3通路的活性，从而延缓PARP抑制剂耐药。
（1）《CDK1 promotes nascent DNA synthesis and induces resistance of cancer cells to DNA-damaging therapeutic agents》
“Moreover, we show that compromised CDK1 activity dramatically increases the efficacy of chemotherapeutic agents that kill cancer cells through perturbing DNA replication, including Olaparib, an FDA approved PARP inhibitor. ”
（2）《PBK drives PARP inhibitor resistance through the TRIM37/NFκB axis in ovarian cancer》
“Additionally, PBK enhanced olaparib resistance of ovarian cancer by regulating the NFκB/TRIM37 axis in vitro and in vivo. In conclusion, PBK confers ovarian cancer resistance to PARPi through activating the TRIM37-mediated NFκB pathway, and targeted inhibition of PBK provided the new therapy to improve PARPi treatment outcomes for ovarian cancer patients.”
（3）《Restored replication fork stabilization, a mechanism of PARP inhibitor resistance, can be overcome by cell cycle checkpoint inhibition》
“Combination therapy with cell cycle checkpoint (ATR, CHK1, and WEE1) inhibitors is being investigated clinically in many cancers, particularly in ovarian cancer, to enhance the efficacy and circumvent resistance to PARPis. ”
（4）《Identification of CDK1, PBK, and CHEK1 as an Oncogenic Signature in Glioblastoma: A Bioinformatics Approach to Repurpose Dapagliflozin as a Therapeutic Agent》
“We used in silico molecular docking to analyze and validate our objective to repurpose Dapagliflozin against CDK1/PBK/CHEK1. Our results showed that Dapagliflozin forms putative conventional hydrogen bonds with CDK1, PBK, and CHEK1 and arrests the cell cycle with the lowest energies as Abemaciclib.”
（5）《Re-purposing clinical kinase inhibitors to enhance chemosensitivity by overriding checkpoints》
In vitro and cell-based assays showed that both the authentic bosutinib and Bos-I inhibited DNA damage checkpoint kinases Chk1 and Wee1
（6）《Attenuation of SRC Kinase Activity Augments PARP Inhibitor-mediated Synthetic Lethality in BRCA2-altered Prostate Tumors》
This work suggests that SRC activation may be a potential mechanism of PARPi resistance and that treatment with SRC inhibitors may overcome this resistance.
（7）“ Bosutinib是一种新型的双重Src/Abl抑制剂，在无细胞试验中IC50分别为1.2 nM 和 1 nM。Bosutinib也可通过阻滞p-ERK、p-S6和p-STAT3的磷酸化来有效地降低PI3K/AKT/mTOR、MAPK/ERK和JAK/STAT3信号通路的活性。”
2、双硫仑抑制ATR，延缓parp抑制剂耐药；肼屈嗪（dnmti）+丙戊酸（hdaci）的表观遗传机制替代药物组合抑制dnmt和hdac，延缓parp抑制剂耐药；氮卓斯汀抑制BET-BRD4从而延缓parp抑制剂耐药；拓扑替康和小檗胺稳定 G—四链体从而延缓parp抑制剂耐药。
（1）《Overcoming Platinum and PARP-Inhibitor Resistance in Ovarian Cancer》
Promising therapeutic strategies include ATR inhibition, epigenetic re-sensitisation through DNMT inhibition, cell cycle checkpoint inhibition, combination with anti-angiogenic therapy, BET inhibition and G-quadruplex stabilisation.
（2）《Targeting the NPL4 Adaptor of p97/VCP Segregase by Disulfiram as an Emerging Cancer Vulnerability Evokes Replication Stress and DNA Damage while Silencing the ATR Pathway》
cellular responses to the CuET-triggered RS are seriously impaired due to concomitant malfunction of the ATRIP-ATR-CHK1 signaling pathway that reflects an unorthodox checkpoint silencing mode through ATR (Ataxia telangiectasia and Rad3 related) kinase sequestration within the CuET-evoked NPL4 protein aggregates.
《Combined treatment of disulfiram with PARP inhibitors suppresses ovarian cancer》
Based on these findings, we propose that Disulfiram reinforces PARPis activity in ovarian cancer cells by improving drug sensitivity. The combined use of Disulfiram and PARPis provides a novel treatment strategy for patients with ovarian cancer.
（3）《Structure investigation, enrichment analysis and structure-based repurposing of FDA-approved drugs as inhibitors of BET-BRD4》
we found that several drugs have better binding affinity than the control candidate lead (+)-JQ1 (Binding affinity = -7.9 kcal/mol), a well-known BRD4 inhibitor. Among the top-ranked drugs, azelastine, a selective histamine H1 receptor antagonist, showed the best binding affinity of -9.3 kcal/mol and showed interactions with several key residues of the acetyl lysine binding pocket. Azelastine may serve as a promising template for further medicinal chemistry.
（4）《G-quadruplex stabilization via small-molecules as a potential anti-cancer strategy》
G-quadruplexes (G4) are secondary four-stranded DNA helical structures consisting of guanine-rich nucleic acids, which can be formed in the promoter regions of several genes under proper conditions. Several cancer cells have been shown to emerge from genomic changes in the expression of crucial growth-regulating genes that allow cells to develop and begin to propagate in an undifferentiated state. Recent attempts have focused on producing treatments targeted at particular protein products of genes that are abnormally expressed. Many of the proteins found are hard to target and considered undruggable due to structural challenges, protein overexpression, or mutations that affect treatment resistance. The utilization of small molecules that stabilize secondary DNA structures existing in several possible oncogenes' promoters and modulate their transcription is a new strategy that avoids some of these problems.
《Targeting RNA G-quadruplex with repurposed drugs blocks SARS-CoV-2 entry》
In silico screening followed by experimental validation identify Topotecan (TPT) and Berbamine (BBM), two clinical approved drugs, as RG4-stabilizing agents with repurposing potential for COVID-19.
3、parp抑制剂不要和长春花生物碱化疗药、极光激酶a抑制剂、PLK抑制剂、蒽环类化疗药联用；联用会削弱彼此的药效。
《BET, SRC, and BCL2 family inhibitors are synergistic drug combinations with PARP inhibitors in ovarian cancer》
addition of rucaparib suppressed the effect of many drugs that target the mitotic spindle and microtubules, including vinca alkaloids, AURKA inhibitors and PLK inhibitors (Supp. Fig. 7c). Also, DNA intercalators such as anthracyclines suppressed the effects of rucaparib. These findings suggest the use of certain chemotherapies in combination with PARPi could antagonise their activity in the clinic.
4、抑制hsp90可延缓parp抑制剂耐药；千金藤素抑制Hsp90α，千金藤素又升白可治疗 parp抑制剂的骨髓抑制副作用，一举两得。
（1）《Combined PARP and HSP90 inhibition: preclinical and Phase 1 evaluation in patients with advanced solid tumours》
Purpose: PARP inhibitor resistance may be overcome by combinatorial strategies with agents that disrupt homologous recombination repair (HRR). Multiple HRR pathway components are HSP90 clients, so that HSP90 inhibition leads to abrogation of HRR and sensitisation to PARP inhibition. We performed in vivo preclinical studies of the HSP90 inhibitor onalespib with olaparib and conducted a Phase 1 combination study.
Patients and methods: Tolerability and efficacy studies were performed in patient-derived xenograft(PDX) models of ovarian cancer. Clinical safety, tolerability, steady-state pharmacokinetics and preliminary efficacy of olaparib and onalespib were evaluated using a standard 3 + 3 dose-escalation design.
Results: Olaparib/onalespib exhibited anti-tumour activity against BRCA1-mutated PDX models with acquired PARPi resistance and PDX models with RB-pathway alterations(CDKN2A loss and CCNE1 overexpression). Phase 1 evaluation revealed that dose levels up to olaparib 300 mg/onalespib 40 mg and olaparib 200 mg/onalespib 80 mg were safe without dose-limiting toxicities. Coadministration of olaparib and onalespib did not appear to affect the steady-state pharmacokinetics of either agent. There were no objective responses, but disease stabilisation ≥24 weeks was observed in 7/22 (32%) evaluable patients including patients with BRCA-mutated ovarian cancers and acquired PARPi resistance and patients with tumours harbouring RB-pathway alterations.
（2）《Interaction of cepharanthine with immobilized heat shock protein 90α (Hsp90α) and screening of Hsp90α inhibitors》
Heat shock protein 90α (Hsp90α) immobilized on aminopropyl silica gels was prepared via the N- or C-terminal, which was termed Hsp90α-NT or Hsp90α-CT, respectively. Binding interactions of biscoclaurine alkaloids (cepharanthine (CEP), berbamine (BBM), isotetrandrine (ITD), and cycleanine (CCN)) with Hsp90α were examined using the Hsp90α-NT or -CT columns by frontal and zonal chromatography studies. The dissociation constants of CEP, BBM, ITD, and CCN to Hsp90α-NT were estimated to be 5.3, 18.6, 46.3, and 159 μM, respectively, by frontal chromatography techniques. Similar results were obtained with the Hsp90α-CT column. These data suggest that these biscoclaurine alkaloids interact with the middle domain of Hsp90α. This was confirmed by demonstrating that CEP competed with endothelial nitric oxide synthase at the middle domain of Hsp90α, where it was shown to have a dissociation constant of 15 nM. Furthermore, the Hsp90α-NT column was applied for preliminary screening of natural Hsp90α inhibitors by zonal chromatography studies.
（3）《千金藤素片说明书》
“本品用于肿瘤病人因放疗化疗引起的白细胞减少症。”
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