The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators

Beider, Katia; Bitner, Hanna; Voevoda-Dimenshtein, Valeria; Rosenberg, Evgenia; Sirovsky, Yaarit; Magen, Hila; Canaani, Jonathan; Ostrovsky, Olga; Shilo, Noya; Shimoni, Avichai; Abraham, Michal; Weiss, Lola; Milyavsky, Michael; Peled, Amnon; Nagler, Arnon

doi:10.1016/j.bcp.2019.07.016

Cited by 14 publications

(12 citation statements)

References 57 publications

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“…Treatment with everolimus inhibited the increase in p21 and the expression of DNA repair genes and mitotic checkpoint regulators, which has been observed in multiple myeloma cells (159), hepatocytes with chronic liver injury (160) and isogenic tumor cell lines (161). Studies have further suggested that the combination of everolimus and olaparib inhibited the growth of tumors, and were performed in clone A, U87-MG xenografts and BRCA2-mutated patient-derived xenografts of breast cancer (162,163).…”

Section: Pi3k-akt-mtorc Pathway Inhibitors and Parpimentioning

confidence: 99%

Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review)

2023

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With the development of precision medicine, targeted therapy has attracted extensive attention. Poly(ADP-ribose) polymerase inhibitors (PARPi) are critical clinical drugs designed to induce cell death and are major antitumor targeted agents. However, preclinical and clinical data have revealed the limitations of PARPi monotherapy. Therefore, their combination with other targeted drugs has become a research hotspot in tumor treatment. Recent studies have demonstrated the critical role of small molecular inhibitors in multiple haematological cancers and solid tumors via cellular signalling modulation, exhibiting potential as a combined pharmacotherapy. In the present review, studies focused on small molecular inhibitors targeting the homologous recombination pathway were summarized and clinical trials evaluating the safety and efficacy of combined treatment were discussed. Contents1. Introduction 2. Receptor tyrosine kinase inhibitors (RTKi) and PARP inhibitors (PARPi) 3. Non-RTKi (JAK-STAT pathway) and PARPi 4. PI3K-AKT-mTORC pathway inhibitors and PARPi 5. RAS/RAF/MEK/ERK pathway inhibitors and PARPi 6. Src inhibitors and PARPi 7. Conclusion and future perspectives

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Section: Pi3k-akt-mtorc Pathway Inhibitors and Parpimentioning

confidence: 99%

Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review)

2023

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“…HDACi have also been combined with several inhibitors of known targets. Combination of PAN with some of the compounds listed in Table 3, such as A-1331952, AZD6244, cyclosporine A (CsA), everolimus (EVL), NVP-AUY922, picropodophyllin (PPP), pterostilbene (Pter), RAD001, S63845, tacrolimus (FK506), venetoclax (Ven) and zolendronic acid (ZOL), led to decreased proliferation in various MM cells, 35,78,80,81,83,[85][86][87][88] including patientderived cells, which was synergistic in some cases 78,80,81,83,[85][86][87][88] (Table 2). Interestingly, decreased proliferation was also seen in MM.1S cells co-cultured with BMSCs, in the presence of PAN and AZD6244, as well as PAN and RAD001, suggesting that the BM microenvironment could not stimulate proliferation, while no effect of the combination was observed in BMSCs alone.…”

Section: In Vitro and In Vivo Studies Of Combinations Containing An H...mentioning

confidence: 99%

Histone deacetylase‐based dual targeted inhibition in multiple myeloma

Ferro

Pantazaka

Athanassopoulos

et al. 2023

Medicinal Research Reviews

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Despite enormous advances in terms of therapeutic strategies, multiple myeloma (MM) still remains an incurable disease with MM patients often becoming resistant to standard treatments. To date, multiple combined and targeted therapies have proven to be more beneficial compared to monotherapy approaches, leading to a decrease in drug resistance and an improvement in median overall survival in patients. Moreover, recent breakthroughs highlighted the relevant role of histone deacetylases (HDACs) in cancer treatment, including MM. Thus, the simultaneous use of HDAC inhibitors with other conventional regimens, such as proteasome inhibitors, is of interest in the field. In this review, we provide a general overview of HDAC‐based combination treatments in MM, through a critical presentation of publications from the past few decades related to in vitro and in vivo studies, as well as clinical trials. Furthermore, we discuss the recent introduction of dual‐inhibitor entities that could have the same beneficial effects as drug combinations with the advantage of having two or more pharmacophores in one molecular structure. These findings could represent a starting‐point for both reducing therapeutic doses and lowering the risk of developing drug resistance.

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“…A synergistic activity of dual HDAC and mTOR inhibition was confirmed in Hodgkin lymphoma and multiple myeloma cell lines [ 210 , 211 ]. A phase I, dose-finding trial for everolimus combined with panobinostat in advanced ccRCC was performed (NCT01582009).…”

Section: Epigenetic-based Therapeutic Opportunities In Ccrccmentioning

confidence: 99%

The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments

Angulo

Manini

López

et al. 2021

Cancers

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Clear cell renal cell carcinoma (ccRCC) is curable when diagnosed at an early stage, but when disease is non-confined it is the urologic cancer with worst prognosis. Antiangiogenic treatment and immune checkpoint inhibition therapy constitute a very promising combined therapy for advanced and metastatic disease. Many exploratory studies have identified epigenetic markers based on DNA methylation, histone modification, and ncRNA expression that epigenetically regulate gene expression in ccRCC. Additionally, epigenetic modifiers genes have been proposed as promising biomarkers for ccRCC. We review and discuss the current understanding of how epigenetic changes determine the main molecular pathways of ccRCC initiation and progression, and also its clinical implications. Despite the extensive research performed, candidate epigenetic biomarkers are not used in clinical practice for several reasons. However, the accumulated body of evidence of developing epigenetically-based biomarkers will likely allow the identification of ccRCC at a higher risk of progression. That will facilitate the establishment of firmer therapeutic decisions in a changing landscape and also monitor active surveillance in the aging population. What is more, a better knowledge of the activities of chromatin modifiers may serve to develop new therapeutic opportunities. Interesting clinical trials on epigenetic treatments for ccRCC associated with well established antiangiogenic treatments and immune checkpoint inhibitors are revisited.

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The mTOR inhibitor everolimus overcomes CXCR4-mediated resistance to histone deacetylase inhibitor panobinostat through inhibition of p21 and mitotic regulators

Cited by 14 publications

References 57 publications

Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review)

Combined PARP inhibitors and small molecular inhibitors in solid tumor treatment (Review)

Histone deacetylase‐based dual targeted inhibition in multiple myeloma

The Role of Epigenetics in the Progression of Clear Cell Renal Cell Carcinoma and the Basis for Future Epigenetic Treatments

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