Everolimus in combination with Imatinib overcomes resistance in Chronic myeloid leukaemia

Alves, Raquel; Gonçalves, Ana Cristina; Jorge, Joana; Alves, Joana; Silva, António Alves da; Freitas-Tavares, Paulo; Costa, Nascimento; Almeida, António; Sarmento‐Ribeiro, Ana Bela

doi:10.1007/s12032-019-1253-5

Cited by 17 publications

(11 citation statements)

References 31 publications

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“…The recognition of the PI3K/AKT/mTOR pathway as an important drug target in oncology led to the approval of PI3K inhibitors (as Idelalisib) and mTOR inhibitors (as an example of Sirolimus) for different neoplasias [ 266 ]. In preclinical studies, Everolimus, an mTOR inhibitor, show promising results overcoming TKI resistance in cell lines and ex vivo samples [ 267 , 268 ]. Based on these results, Sirolimus (NCT00776373) and Everolimus (NCT00081874 and NCT01188889) were evaluated in phase I and II clinical trials in CML patients [ 269 ].…”

Section: Therapeutic Approaches Against Resistancementioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

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Resistance to targeted therapies is a complex and multifactorial process that culminates in the selection of a cancer clone with the ability to evade treatment. Chronic myeloid leukemia (CML) was the first malignancy recognized to be associated with a genetic alteration, the t(9;22)(q34;q11). This translocation originates the BCR-ABL1 fusion gene, encoding the cytoplasmic chimeric BCR-ABL1 protein that displays an abnormally high tyrosine kinase activity. Although the vast majority of patients with CML respond to Imatinib, a tyrosine kinase inhibitor (TKI), resistance might occur either de novo or during treatment. In CML, the TKI resistance mechanisms are usually subdivided into BCR-ABL1-dependent and independent mechanisms. Furthermore, patients’ compliance/adherence to therapy is critical to CML management. Techniques with enhanced sensitivity like NGS and dPCR, the use of artificial intelligence (AI) techniques, and the development of mathematical modeling and computational prediction methods could reveal the underlying mechanisms of drug resistance and facilitate the design of more effective treatment strategies for improving drug efficacy in CML patients. Here we review the molecular mechanisms and other factors involved in resistance to TKIs in CML and the new methodologies to access these mechanisms, and the therapeutic approaches to circumvent TKI resistance.

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Section: Therapeutic Approaches Against Resistancementioning

confidence: 99%

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Alves

Gonçalves

Rutella

et al. 2021

Cancers

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“…As previously reported, metformin induced cytotoxicity by promoting cell-cycle arrest in the G0/G1 (SW480, K7M2, and MG63 cells) [52][53][54] or G2/M (HCT116 p53 −/− , 143B, and U20S cells) phase [54,55], and everolimus was involved in G0/G1-phase (MCF-7, BT474, and K562 cells) [56,57] and G2/M-phase arrest (Rb MCF-7 and gemcitabine-resistant MIAPaCa cells) [58,59]. In the present study, metformin combined with everolimus also caused G0/G1-phase cell-cycle arrest in CaSki and C33A cells, in addition to a higher percentage of cells in the sub-G1 phase in CaSki cells, but not in C33A cells (Figure 3).…”

Section: Discussionmentioning

confidence: 72%

Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo

Chen

Yang

et al. 2021

Cancers

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Cervical cancer is globally the fourth most common cancer in women. Metformin is a widely used drug for the treatment of type II diabetes and has been shown to possess important anticancer properties in cervical cancer. Everolimus is an mTOR inhibitor and is widely used to treat NETs, RCC, TSC, and breast cancers. The present study investigated the anticancer effects of metformin and everolimus in cervical cancer, when used alone or in combination. CaSki and C33A human cervical cancer cells were treated with different concentrations of everolimus alone or in combination with metformin. Cell viability was assessed using a CCK-8 assay. Cell apoptosis, cell-cycle, and mtROS analyses were conducted using flow cytometry. Target protein levels were analyzed by Western blotting. Related mechanisms were confirmed using appropriate inhibitors (z-VAD-fmk and BIRB796). The in vitro results were further confirmed in a xenograft tumor study. Both metformin and everolimus, when used alone, were moderately effective in inhibiting cell proliferation and inducing cell apoptosis of CaSki and C33A cells. When used in combination, these two drugs synergistically inhibited the growth of human cervical cancer cells and xenografts in nude mice, promoted sub-G1- and G0/G1-phase cell-cycle arrest, and enhanced mtROS production. The protein expressions of PI3K (p110α) and p-AKT were significantly downregulated, while P27, P21, p-p38, p-ERK, and p-JNK were upregulated following combined treatment. These results revealed that metformin potentiates the anticancer effect of everolimus on cervical cancer, and combination treatment with metformin and everolimus provides a novel therapeutic strategy for patients with cervical cancer.

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“…In a previous report by Lu et al (2017) a gene set enrichment analysis identified the activation of mTOR signaling in oxaliplatin-treated early passaged cell lines and patient-derived xenografts of colon cancer, and co-treatment of oxaliplatin with an mTOR inhibitor demonstrated an additive effect in the in vitro and in vivo experiments. ELM is a well-established mTOR inhibitor that has been suggested as an ideal combination regimen with chemotherapy for the management of cancers (Li et al, 2016;Generali et al, 2017;Alves et al, 2019). A clinical trial study has also indicated that the combination of ELM and multiagent chemotherapy was well-tolerated in patients with acute lymphoblastic leukemia (Place et al, 2018).…”

Section: Discussionmentioning

confidence: 99%

“…Everolimus (ELM) is a commonly used antagonist of mTOR that has shown tumor-suppressing functions in cancer management (Falkowski and Woillard, 2019). Interestingly, cotreatment of ELM with imatinib was found to reduce the imatinib resistance in chronic myeloid leukemia (Alves et al, 2019). In addition, ELM was found to overcome the gemcitabine resistance of PC cells and induce cell apoptosis (Peng and Dou, 2017).…”

Section: Introductionmentioning

confidence: 99%

Co-treatment With Everolimus, an mTOR-Specific Antagonist, or Downregulation of ELK1 Enhances the Sensitivity of Pancreatic Cancer Cells to Genistein

Kuang

Yang

et al. 2021

Front. Cell Dev. Biol.

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Genistein is a natural isoflavone with pharmacological or potentially anti-tumor properties. However, the resistance of cancer cells to genistein remains a major obstacle. This study focused on the mechanism implicated in the resistance of pancreatic cancer (PC) cells to genistein and the mechanism of action. First, key molecules and signaling pathways related to genistein resistance in PC cells were explored using bioinformatics tools. DEP domain containing MTOR interacting protein (DEPTOR), a typical inhibitor of the mammalian target of rapamycin (mTOR) signaling, was predicted to be poorly expressed in the genistein-resistant PC cells. Thereafter, genistein-resistant PC cells (Panc-1 and PaCa) were constructed. Altered expression of DEPTOR was introduced in cells, and everolimus (ELM), an mTOR-specific antagonist, was administrated in cells as well to examine their roles in genistein resistance. The cell apoptosis was examined in vitro and in vivo in mouse xenograft tumors. The upstream regulator of DEPTOR was predicted via bioinformatic tools. The bioinformatic analyses showed that the PI3K/AKT/mTOR signaling pathway was activated in the setting of DEPTOR downregulation in genistein-resistant PC cells. DEPTOR overexpression reduced the 50% inhibiting concentration (IC50) of genistein in PC cells and suppressed mTOR phosphorylation, and it increased caspase-3 activity, LDH release and apoptosis in PC cells. ELM treatment enhanced the sensitivity of PC cells to genistein in vitro and it strengthened the tumor-eliminating role of genistein in mice. ETS transcription factor ELK1 (ELK1), a transcription factor that negatively regulated DEPTOR transcription, was suppressed by genistein. Upregulation of ELK1 suppressed DEPTOR transcription and reduced the genistein sensitivity of cells, and it also blocked the genistein-sensitizing roles of ELM in PC cells. In conclusion, this study demonstrated that ELK1 reduces DEPTOR transcription, leading to mTOR phosphorylation and the drug resistance of PC cells.

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Everolimus in combination with Imatinib overcomes resistance in Chronic myeloid leukaemia

Cited by 17 publications

References 31 publications

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Resistance to Tyrosine Kinase Inhibitors in Chronic Myeloid Leukemia—From Molecular Mechanisms to Clinical Relevance

Metformin Potentiates the Anticancer Effect of Everolimus on Cervical Cancer In Vitro and In Vivo

Co-treatment With Everolimus, an mTOR-Specific Antagonist, or Downregulation of ELK1 Enhances the Sensitivity of Pancreatic Cancer Cells to Genistein

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