Dataset Information

Stellettin B Sensitizes Glioblastoma to DNA-Damaging Treatments by Suppressing PI3K-Mediated Homologous Recombination Repair.

ABSTRACT: Glioblastoma (GBM) is the most aggressive type of cancer. Its current first-line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage-inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA-damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in vitro and in vivo. Mechanistically, STELB inhibits the expression of homologous recombination repair (HR) factors BRCA1/2 and RAD51 by promoting the degradation of PI3Kα through the ubiquitin-proteasome pathway; and the induced HR deficiency then leads to augmented DNA damage and cell death. It is further demonstrated that STELB has the potential to rapidly penetrate the blood-brain barrier to exert anti-GBM effects in the brain, based on zebrafish and nude mouse orthotopic xenograft tumor models. The study provides strong evidence that STELB represents a promising drug candidate to improve GBM therapy in combination with DNA-damaging treatments.

SUBMITTER: Peng X

PROVIDER: S-EPMC9875605 | biostudies-literature | 2023 Jan

REPOSITORIES: biostudies-literature

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Stellettin B Sensitizes Glioblastoma to DNA-Damaging Treatments by Suppressing PI3K-Mediated Homologous Recombination Repair.

Peng Xin X Zhang Shaolu S Wang Yingying Y Zhou Zhicheng Z Yu Zixiang Z Zhong Zhenxing Z Zhang Liang L Chen Zhe-Sheng ZS Claret Francois X FX Elkabets Moshe M Wang Feng F Sun Fan F Wang Ran R Liang Han H Lin Hou-Wen HW Kong Dexin D

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20221201 3

Glioblastoma (GBM) is the most aggressive type of cancer. Its current first-line postsurgery regimens are radiotherapy and temozolomide (TMZ) chemotherapy, both of which are DNA damage-inducing therapies but show very limited efficacy and a high risk of resistance. There is an urgent need to develop novel agents to sensitize GBM to DNA-damaging treatments. Here it is found that the triterpene compound stellettin B (STELB) greatly enhances the sensitivity of GBM to ionizing radiation and TMZ in v ...[more]

PMID: 36453577

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Project description:BackgroundOvarian cancer (OC), particularly high-grade serous ovarian carcinoma (HGSOC), is the leading cause of mortality from gynecological malignancies worldwide. Despite the initial effectiveness of treatment, acquired resistance to poly(ADP-ribose) polymerase inhibitors (PARPis) represents a major challenge for the clinical management of HGSOC, highlighting the necessity for the development of novel therapeutic strategies. This study investigated the role of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), a pivotal regulator of glycolysis, in PARPi resistance and explored its potential as a therapeutic target to overcome PARPi resistance.MethodsWe conducted in vitro and in vivo experiments to assess the role of PFKFB3 in OC and its impact on PARPi resistance. We analyzed PFKFB3 expression and activity in primary OC tissues and cell lines using western blotting and immunohistochemistry. CRISPR-Cas9 and pharmacological inhibitors were employed to inhibit PFKFB3, and the effects on PARPi resistance, homologous recombination (HR) repair efficiency, and DNA damage were evaluated. RNA sequencing and proximity labeling were employed to identify the molecular mechanisms underlying PFKFB3-mediated resistance. The in vivo efficacy of PARPi and PFK158 combination therapy was evaluated in OC xenograft models.ResultsPFKFB3 activity was significantly elevated in OC tissues and associated with PARPi resistance. Inhibition of PFKFB3, both genetically and pharmacologically, sensitized OC cells to PARPis, impaired HR repair and increased DNA damage. Proximity labeling revealed replication protein A3 (RPA3) as a novel PFKFB3-binding protein involved in HR repair. In vivo, the combination of PFK158 and olaparib significantly inhibited tumor growth, increased DNA damage, and induced apoptosis in OC xenografts without exacerbating adverse effects.ConclusionsOur findings demonstrate that PFKFB3 is crucial for PARPi resistance in OC. Inhibiting PFKFB3 sensitizes HR-proficient OC cells to PARPis by impairing HR repair, leading to increased DNA damage and apoptosis. PFKFB3 represents a promising therapeutic target for overcoming PARPi resistance and improving outcomes in OC patients.

Project description:BackgroundHigh-grade serous ovarian carcinomas (HGSCs) are a heterogeneous subtype of epithelial ovarian cancers and include serous cancers arising in the fallopian tube and peritoneum. These cancers are now subdivided into homologous recombination repair (HR)-deficient and proficient subgroups as this classification impacts on management and prognosis. PARP inhibitors (PARPi) have shown significant clinical efficacy, particularly as maintenance therapy following response to platinum-based chemotherapy in BRCA-mutant or homologous recombination (HR)-deficient HGSCs in both the 1st and 2nd line settings. However, PARPi have limited clinical benefit in HR-proficient HGSCs which make up almost 50% of HGSC and improving outcomes in these patients is now a high priority due to the poor prognosis with ineffectiveness of the current standard of care. There are a number of potential lines of investigation including efforts in sensitizing HR-proficient tumors to PARPi. Herein, we aimed to develop a novel combination therapy by targeting SSRP1 using a small molecule inhibitor CBL0137 with PARPi in HR-proficient HGSCs.Experimental designWe tested anti-cancer activity of CBL0137 monotherapy using a panel of HGSC cell lines and patient-derived tumor cells in vitro. RNA sequencing was used to map global transcriptomic changes in CBL0137-treated patient-derived HR-proficient HGSC cells. We tested efficacy of CBL0137 in combination with PARPi using HGSC cell lines and patient-derived tumor cells in vitro and in vivo.ResultsWe show that SSRP1 inhibition using a small molecule, CBL0137, that traps SSRP1 onto chromatin, exerts a significant anti-growth activity in vitro against HGSC cell lines and patient-derived tumor cells, and also reduces tumor burden in vivo. CBL0137 induced DNA repair deficiency via inhibition of the HR repair pathway and sensitized SSRP1-high HR-proficient HGSC cell lines and patient-derived tumor cells/xenografts to the PARPi, Olaparib in vitro and in vivo. CBL0137 also enhanced the efficacy of DNA damaging platinum-based chemotherapy in HGSC patient-derived xenografts.ConclusionOur findings strongly suggest that combination of CBL0137 and PARP inhibition represents a novel therapeutic strategy for HR-proficient HGSCs that express high levels of SSRP1 and should be investigated in the clinic.

Dataset Information

Stellettin B Sensitizes Glioblastoma to DNA-Damaging Treatments by Suppressing PI3K-Mediated Homologous Recombination Repair.

Publications

Stellettin B Sensitizes Glioblastoma to DNA-Damaging Treatments by Suppressing PI3K-Mediated Homologous Recombination Repair.

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