Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma

Miklja, Zachary; Yadav, Viveka Nand; Cartaxo, Rodrigo; Siada, Ruby; Thomas, Chase; Cummings, Jessica; Mullan, Brendan; Stallard, Stefanie; Paul, Alyssa; Bruzek, Amy K.; Wierzbicki, Kyle; Yang, Tao; García, Teresa; Wolfe, Ian; Leonard, Marcia; Robertson, Patricia L.; Garton, Hugh; Wahl, Daniel R.; Parmar, Hemant; Sarkaria, Jann N.; Kline, Cassie; Mueller, Sabine; Nicolaides, Theodore; Glasser, Chana L.; Leary, Sarah; Venneti, Sriram; Kumar‐Sinha, Chandan; Chinnaiyan, Arul M.; Mody, Rajen; Pai, Manjunath P.; Phoenix, Timothy N.; Marini, Bernard L.; Koschmann, Carl

doi:10.1172/jci133310

Cited by 51 publications

(46 citation statements)

References 36 publications

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“…Our previous study reported that the mTOR pathway was upregulated in CML, and rapamycin arrested cells at the G 0 /G 1 phase and increased apoptosis in K562 cells ( 8 ). In addition, a mTOR inhibitor, everolimus is currently being investigated as an anticancer agent due to its potential action by inhibiting tumor cell proliferation, and has been used in clinical trials ( 25 – 27 ). However, it has been reported that everolimus plus only or Imatinib demonstrate limited activity in progressing advanced cancer types ( 28 , 29 ), and the clinical application of everolimus does not exert the same effect as that in in vitro experiments.…”

Section: Discussionmentioning

confidence: 99%

Dual PI3K/mTOR inhibitor NVP‑BEZ235 decreases the proliferation of doxorubicin‑resistant K562 cells

Wang

et al. 2021

Mol Med Rep

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Acute myelogenous leukemia (AML) is frequently accompanied by a poor prognosis. The majority of patients with AML will experience recurrence due to multiple drug resistance. Our previous study reported that targeting the mTOR pathway may increase cell sensitivity to doxorubicin (Doxo) and provide an improved therapeutic approach to leukemia. However, the effect and mechanism of action of NVP-BEZ235 (BEZ235), a dual inhibitor of PI3K/mTOR, on Doxo-resistant K562 cells (K562/A) is yet to be elucidated. Therefore, the aim of the present study was to investigate the effects of BEZ235 on K562/A cell proliferation. K562/A cells was investigated using CCK-8, flow cytometry and western blotting, following BEZ235 treatment. It was observed that BEZ235 significantly decreased the viability of K562/A cells. In addition, BEZ235 arrested K562/A cells at the G 0 /G 1 phase, and reduced the protein expression levels of CDK4, CDK6 and cyclin D1. Apoptotic cells were more frequently detected in K562/A cells treated with BEZ235 compared with the control group (12.97±0.91% vs. 7.37±0.42%, respectively; P<0.05). Cells treated with BEZ235 exhibited downregulation of Bcl-2 and upregulation of Bax. Furthermore, BEZ235 treatment markedly decreased the activation of the PI3K/AKT/mTOR pathway and its downstream effectors. Thus, these results demonstrated that BEZ235 inhibited cell viability, induced G 0 /G 1 arrest and increased apoptosis in K562/A cells, suggesting that BEZ235 may reverse Doxo resistance in leukemia cells. Therefore, targeting the PI3K/mTOR pathway may be of value as a novel therapeutic approach to leukemia.

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Section: Discussionmentioning

confidence: 99%

Dual PI3K/mTOR inhibitor NVP‑BEZ235 decreases the proliferation of doxorubicin‑resistant K562 cells

Wang

et al. 2021

Mol Med Rep

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“…To our knowledge, this triple combination has not been tested in ovarian cancer either in preclinical or clinical study. Everolimus has been described to improve the efficacy of dasatinib in PDGFRα-driven glioma [ 63 ]. The combination of sunitinib and everolimus is currently under phase I study in patients with metastatic renal cell carcinoma.…”

Section: Discussionmentioning

confidence: 99%

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer

Wen

Han

Dellinger

et al. 2020

Cancers

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More effective therapy is needed to improve the survival of patients with advanced and recurrent ovarian cancer. Preclinical and early clinical studies with single molecular targeted agents have shown limited antitumor activity in ovarian cancer, likely due to compensation by alternative growth/survival pathways. An emerging strategy in overcoming resistance is to combine inhibitors targeting multiple pathways. In this study, we used a novel strategy of combining several FDA-approved targeted drugs, including sunitinib, dasatinib, and everolimus, in human ovarian cancers. Combination of the tyrosine kinase inhibitor sunitinib with the SRC inhibitor dasatinib showed synergistic anti-tumor activity in human ovarian cancer cells. The increased activity was associated with inhibition of the STAT3, SRC, and MAPK signaling pathways, but not AKT signaling. To inhibit the PI3K/AKT/mTOR pathway, we added the mTOR inhibitor everolimus, which further increased anti-tumor activity in cells. Combined treatment with sunitinib, dasatinib, and everolimus also resulted in greater inhibition of human ovarian tumor growth in mice. Furthermore, the triple combination also synergistically increased the anti-tumor activity of paclitaxel, both in vitro and in vivo. Taken together, our results demonstrate that simultaneous inhibition of several signaling pathways results in better anti-tumor activity compared to inhibiting any of these signaling pathways alone.

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“…In addition, the immune competency status of these IUE glioma mouse models also provides an in vivo system to examine immune-modulatory and immunotherapy strategies. Our recent studies have shown that an IUE-based high-grade glioma is a powerful approach, revealing that the efficacy of dasatinib treatment of Pdgfra D842V + DN-p53 high-grade glioma is enhanced with everolimus (82). The results suggest a promising route for improving targeted therapy for high-grade glioma patient with the driver mutation of PDGFα and p53.…”

Section: In Utero Electroporation-based Glioma Mouse Modelsmentioning

confidence: 92%

Integration of Molecular Analysis, Cutting-edge Mouse Genetic Models and Proton Therapy to Improve Outcomes for Glioma Patients

Sengupta

Pater

Krummel

et al. 2021

Gliomas

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Despite recent advances in general cancer treatment, glioblastoma remains among the most lethal of human malignancies. Even with aggressive multimodal radiation and chemotherapy after surgery, glioblastoma recurs with a bleak prognosis. Decades of research focused on strategies such as increasing radiation sensitivity and interference with oncogenic signal transduction have yielded only incremental improvements at best. This is due in part to the radioresistance of glioblastoma and molecular heterogeneity of tumor cells. We hypothesize is that the development of more effective glioblastoma therapies will require: (i) a more accurate molecular analysis of glioblastoma so as to predict response to therapy; (ii) better genetically engineered mouse models, which can faithfully recapitulate human glioblastoma and the tumor microenvironment to test new approaches and (iii) development and application of more accurate and focused methods to deliver sustained high energy particles to glioblastoma tumor sites. This chapter describes the current state-of-the-art molecular analysis approaches, latest in glioma mouse modelling, and advances in the application of proton therapy treatment and research. By integrating basic and clinical research with cutting-edge technologies, a mechanistic understanding of glioblastoma therapy resistance and pathogenesis and the development of new therapeutics to overcome the therapeutic resistance of glioblastoma will be advanced.

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Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma

Cited by 51 publications

References 36 publications

Dual PI3K/mTOR inhibitor NVP‑BEZ235 decreases the proliferation of doxorubicin‑resistant K562 cells

Dual PI3K/mTOR inhibitor NVP‑BEZ235 decreases the proliferation of doxorubicin‑resistant K562 cells

Synergistic Anti-Tumor Activity by Targeting Multiple Signaling Pathways in Ovarian Cancer

Integration of Molecular Analysis, Cutting-edge Mouse Genetic Models and Proton Therapy to Improve Outcomes for Glioma Patients

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