Synergistic Killing of Leukemic Cells by Small Molecule Inhibitors of the Pim Protein Kinases and Inactivators of Additional Signal Transduction Pathways.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 409-409
Author(s):  
Yingwei Lin ◽  
Zanna M Beharry ◽  
Elizabeth G Hill ◽  
Jin H. Song ◽  
Wenxue Wang ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Cell Growth ◽  
Small Molecule ◽  
Single Agent ◽  
Signal Transduction Pathways ◽  
Pim Kinases ◽  
Cycle Arrest ◽  
Mtorc1 Pathway ◽  
P70 S6k

Abstract Abstract 409 The serine/threonine Pim kinases are up regulated in specific hematologic neoplasms, and play an important role in key signal transduction pathways, including those regulated by c-Myc, N-Myc, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. Pim protein kinases were first identified as a proviral integration site in c-Myc overexpressor mice and function to greatly enhance lymphoma development. Here we demonstrate that SMI-4a, a novel benzylidene-thiazolidine-2, 4-dione small molecule inhibitor of the Pim kinases supplied by Vortex Biotechnology (Mt. Pleasant, SC), kills a wide range of both myeloid and lymphoid cell lines with precursor T-cell lymphoblastic leukemia/lymphoma (pre T-LBL/T-ALL) being the most sensitive. Incubation of pre T-LBL cells with SMI-4a induced G1 phase cell cycle arrest secondary to a dose dependent induction of p27Kip1, apoptosis through the mitochondrial pathway, inhibition of mTORC1 pathway based on decreases in phosphorylation of p70 S6K and 4E-BP1, two substrates of this enzyme, and down regulation of c-myc. We demonstrate that treatment with 60 mg/kg twice daily by oral gavage of SMI-4a inhibits subcutaneous growth of pre T-LBL tumors by an average of 47.9% (p< .05) in immuno-deficient animals without notable toxicity to weight, blood counts, cell morphology, or blood chemistries. To enhance the killing effect of SMI-4a we have examined a number of potential combination therapies. First, because we find in animals and cell culture that single agent SMI-4a treatment up regulates the ERK pathway and in the spleen and thymus of Pim1/2/3 knock out mice there is increased phosphorylation of ERK1/2, we combined SMI-4a and a MEK1/2 inhibitor, U0126 or PD184352. Our results demonstrate that this combination is highly synergistic in killing pre T-LBL cells in culture. Secondly, because SMI-4a shares a number of important properties with γ-secretase inhibitors (GSI), Notch1 pathway inhibitor, including inhibition of pre T-LBL cell growth, cell cycle arrest, induction of p27Kip1, mTORC1 inhibition, and c-Myc down regulation, we tested the possibility that these agents could be synergistic. We find that single agent treatment with SMI-4a at 5 μM or treatment with the GSI Z-IL-CHO at 10 μM kills less than 20% of pre T-LBL cells, whereas in combination these drugs kill 78% of these cells, suggesting a high degree of synergy. Finally, because SMI-4a inhibits the mTORC1 pathway decreasing the phosphorylation of two mTOR substrates, p70 S6K and 4E-BP1, and because Pim plays an essential role in the FLT3/ITD signaling pathway, we examined the activity of SMI-4a with or without rapamycin in myeloid leukemic MV4-11 carrying both MLL-AF4 and FLT3-ITD and the RS4-11 cell line containing only MLL-AF4. We find that these two agents are highly synergistic in culture. SMI-4a alone inhibited growth 18% and rapamycin 40% but when combined 76% of the cell growth was blocked. SMI-4a had no effect on RS 4-11 cells. Our results demonstrate that unique combinations of a potent Pim inhibitor, SMI-4a, and small molecule blockade of either the mTORC1, ERK or Notch pathways has promise as a novel combination strategies for the treatment of human leukemia. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Iodide- and Glucose-Handling Gene Expression Regulated by Sorafenib or Cabozantinib in Papillary Thyroid Cancer

2015 ◽  
Vol 100 (5) ◽  
pp. 1771-1779 ◽  
Author(s):  
Maomei Ruan ◽  
Min Liu ◽  
Qianggang Dong ◽  
Libo Chen
Keyword(s):  
Gene Expression ◽  
Cell Cycle ◽  
Signal Transduction ◽  
Cell Proliferation ◽  
Thyroid Cancer ◽  
Western Blot ◽  
Glucose Transporter ◽  
Signal Transduction Pathways ◽  
Papillary Thyroid ◽  
Cycle Arrest

Abstract Context: The aberrant silencing of iodide-handling genes accompanied by up-regulation of glucose metabolism presents a major challenge for radioiodine treatment of papillary thyroid cancer (PTC). Objective: This study aimed to evaluate the effect of tyrosine kinase inhibitors on iodide-handling and glucose-handling gene expression in BHP 2-7 cells harboring RET/PTC1 rearrangement. Main Outcome Measures: In this in vitro study, the effects of sorafenib or cabozantinib on cell growth, cycles, and apoptosis were investigated by cell proliferation assay, cell cycle analysis, and Annexin V-FITC apoptosis assay, respectively. The effect of both agents on signal transduction pathways was evaluated using the Western blot. Quantitative real-time PCR, Western blot, immunofluorescence, and radioisotope uptake assays were used to assess iodide-handling and glucose-handling gene expression. Results: Both compounds inhibited cell proliferation in a time-dependent and dose-dependent manner and caused cell cycle arrest in the G0/G1 phase. Sorafenib blocked RET, AKT, and ERK1/2 phosphorylation, whereas cabozantinib blocked RET and AKT phosphorylation. The restoration of iodide-handling gene expression and inhibition of glucose transporter 1 and 3 expression could be induced by either drug. The robust expression of sodium/iodide symporter induced by either agent was confirmed, and 125I uptake was correspondingly enhanced. 18F-fluorodeoxyglucose accumulation was significantly decreased after treatment by either sorafenib or cabozantinib. Conclusions: Sorafenib and cabozantinib had marked effects on cell proliferation, cell cycle arrest, and signal transduction pathways in PTC cells harboring RET/PTC1 rearrangement. Both agents could be potentially used to enhance the expression of iodide-handling genes and inhibit the expression of glucose transporter genes.

The Acquirement Of Rituximab Resistance Is Associated With De-Regulation Of The PI3K/Akt/mTOR Signaling Pathway Leading To Chemotherapy Resistance In Burkitt Lymphoma Pre-Clinical Models

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5144-5144 ◽  
Author(s):  
Sarah Frys ◽  
Andrew Skomra ◽  
Natalie M Czuczman ◽  
Cory Mavis ◽  
Delphine C.M. Rolland ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Flow Cytometry ◽  
Cell Viability ◽  
Cell Lines ◽  
Burkitt Lymphoma ◽  
Chemotherapy Resistance ◽  
Signal Transduction Pathways ◽  
Mtor Signaling Pathway ◽  
Cycle Arrest

Abstract Treatment with multi-agent chemotherapy regimens has significantly improved survival in pediatric Burkitt Lymphoma (BL) leading to long-term survival in over 80% of cases. The incorporation of rituximab in the treatment of pediatric B-cell non-Hodgkin lymphoma (B-NHL) has been slower than in adults, but may improve clinical outcomes in high risk pediatric BL patients when combined with chemotherapy regimens. On the other hand, BL patients with primary refractory or relapsed disease have a dismal prognosis, stressing the need to identify the mechanism(s) resulting in chemotherapy/rituximab resistance and to develop novel therapeutic approaches. To this end, we exposed a BL cell line (Raji) to escalating doses of rituximab with or without human serum and generated/characterized several BL rituximab-resistant (Raji 7R and Raji 8RH) (RRCL) or rituximab-chemotherapy resistant (Raji 2R and Raji 4RH) (RCRCL) cell lines. Subsequently, we screened for aberrant activation of signal transduction pathways between RSCL (Raji), RRCL (Raji 7R and Raji 8RH), or RCRCL (Raji 2R and Raji 4RH) in an attempt to define what pathways were associated with resistance to both rituximab and chemotherapy agents. This was accomplished by the analysis of phosphorylation patterns on key-regulatory members of pre-defined signal transduction pathways using Western blotting, phospho-flow cytometry studies and phosphoproteomics. Effects on cell viability or cell cycle distribution of RRCL or RCRCL following pharmacological inhibition of key-regulatory pathways identified was then performed using the alamar blue reduction assay or flow cytometry respectively. While total Akt (Protein kinase B) expression was similar between all the types of BL cell lines tested, we found that RCRCL (Raji 2R and Raji 4RH) had an increase in basal phosphorylation levels of Akt at the Ser473 and Thr308 phosphorylation sites when compared to RSCL (Raji cells) or RRCL (Raji 7R and Raji 8RH). These findings were confirmed by phospho-flow cytometry studies. Phosphoproteomic analysis comparing Raji (RSCL) against Raji 4RH (RCRCL) cells identified an increase of at least 2 fold in the phosphorylation of 315 proteins in RCRCL including several direct targets of AKT such as GSK3B, WEE1, FOXO1 and PRAS40. Altered phosphorylation of multiple Akt/mTOR downstream proteins (BAD, 4EBP1, GSK3B and ERK) was detected by western blot in RCRCLs (Raji 2R and Raji 4RH) compared to RSCL and RRCLs. In vitro exposure of RCRCL (Raji 2R and Raji 4RH) to escalating doses of MK-2206, a selective Akt inhibitor, or idelalisib, a selective PI3 kinase delta inhibitor, resulted in a dose- and time-dependent decrease in cell viability of RCRCL and to a lesser degree RRCL and RSCL (RCRCL vs. RRCL/RSCL, p<0.05). The IC50 of MK-2206 was lower in RCRCL (Raji-2R = 2.6µM and Raji-4RH = 3.2µM) than in RSCL (Raji= 4.4µM) or RRCL (Raji 7R = 4.0µM and Raji 8RH = 5.2µM). Similarly, the IC50 for idelalisib was lower in RCRCL (Raji-2R = 61µM and Raji-4RH = 149µM) than in RSCL (Raji= 341µM) or RRCL (Raji 7R = 195µM and Raji 8RH = 318µM). In addition, PI3K/Akt/m-TOR inhibition with either MK-2206 or idelalisib induced cell cycle arrest in G1 phase in RSCL/RRCL, but G2/M cell cycle arrest was observed in RCRCL. In BL cells pre-treated with idelalisib (10µM and 50µM) for 24 hours prior to exposure to doxorubicin (1µM, 10µM or 20µM) for 48 hours, the RCRCL Raji 2R exhibited an increased sensitivity to doxorubicin compared to non-idelalisib exposed controls (untreated vs. idelalisib 10µM vs. idelalisib 50µM: doxorubicin 10µM=78% vs. 69% vs. 56%, p<0.05; doxorubicin 20µM=61% vs. 49% vs. 43%, p<0.05). Raji and Raji 7R cells pre-treated with idelalisib did not exhibit an increase in doxorubicin sensitivity. Together our data suggest that constitutive phosphorylation/activation of the PI3K/Akt signal transduction pathway is associated with the development of resistance and may play a role in shared resistant pathways that lead to the acquirement of chemotherapy resistance observed in some rituximab-resistant cell lines. Additionally, inhibition of the PI3K/Akt/mTOR pathway may partially re-sensitize chemotherapy resistant cells to the cytotoxic effects of chemotherapeutic agents. Targeting the PI3K/Akt/mTOR signaling pathway may be clinically relevant in some patients with relapsed/refractory BL. (Research supported by a grant from Hyundai Hope on Wheels and a St. Baldrick’s Foundation Scholar Award) Disclosures: Czuczman: Genetech, Onyx, Celgene, Astellas, Millennium, Mundipharma: Advisory Committees Other.

Effect of a small-molecule MDM2/MDMX inhibitor on cell cycle arrest and apoptosis in breast cancer cells.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e22096-e22096
Author(s):  
Qian Qian Geng ◽  
En Xiao Li ◽  
Dan Feng Dong ◽  
Yin Ying Wu ◽  
Jie Wang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Cell Growth ◽  
Cell Cycle Arrest ◽  
Cancer Cells ◽  
Small Molecule ◽  
Breast Cancer Cells ◽  
Breast Cancer Cell Lines ◽  
Cycle Arrest ◽  
Mdm2 Inhibitor

e22096 Background: The MDM2 inhibitor which disrupted the MDM2-p53 interaction made little effort on the activation of p53 for breast cancer treatments, due to MDMX over expression. Previously a small molecule inhibitor targeting at MDM2 and MDMX had been successfully synthesized. We tested anti-tumor activity of the small molecule MDM2/MDMX inhibitor, compared with nutlin-3α, a well characterized MDM2 inhibitor, in the wild-type (wt) and mutant (mt) p53 breast cancer cell lines. Methods: Human breast cancer cell lines MCF-7 (wt-p53), ZR-7530 (wt-p53), BT-474 (mt-p53) and MDA-MB-231 (mt-p53) were cultured and treated with the small molecule MDM2/MDMX inhibitor, nutlin-3α or phosphate buffer solution (PBS) for 48 hrs separately. MTT for cell viability, FCM for cell cycle arrest and Annexin V FITC/PI for cell apoptosis were performed. The mechanism of antitumor activity of the small molecule MDM2/MDMX inhibitor was determined by Western-Blot analysis. Results: The inhibitor of MDM2 and MDMX inhibited cell growth and induced cell cycle arrest and apoptosis in mt-p53 breast cancer cells while nutlin-3α cannot. In the breast cancer cells with wt-p53, both of them inhibited cell growth, induced cell cycle arrest and apoptosis, but MDM2/MDMX inhibitor was proven to be more effective. Western Blot revealed that there was higher level of p53 expression in breast cancer cells treated with MDM2/MDMX inhibitor than nutlin-3α. The marked increases in p21, Bax and PUMA expressions were abserved in both wt-p53 and mt-p53 breast cancer cells which indicated that the small molecule MDM2/MDMX inhibitor induced cell apoptosis through p21, Bax and PUMA over expressions. Conclusions: The small molecule MDM2/MDMX inhibitor would be able to suppress cell proliferation, induce cell cycle arrest and apoptosis, activate p53 more effective than nutlin-3α in breast cancer cells, no matter with p53 status. P21, Bax and PUMA were involved in the mechanism of apoptosis induction. The inhibitor of targeting at both MDM2 and MDMX will be a novel treatment for breast cancer p53-independent status in the future.

Multiple Strategies Based on MEK, mTOR and BCL-2 Signal Transduction Inhibition in Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5034-5034
Author(s):  
Maria Rosaria Ricciardi ◽  
Samantha Decandia ◽  
Sara Santinelli ◽  
Chiara Gregorj ◽  
Fabiana De Cave ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Signal Transduction ◽  
Cell Growth ◽  
Growth Inhibition ◽  
Cell Lines ◽  
Current Evidence ◽  
Signal Transduction Pathways ◽  
Apoptosis Induction ◽  
Term Survival ◽  
Erk Phosphorylation

Abstract In spite of improvements in the last decade, relapses still occurs in the majority of ALL patients, with a long-term survival rate of only 30–40%. Recently, small-molecule inhibitors have been developed for targeting deregulated signal transduction pathways involved in proliferation and apoptosis. Current evidence identifies the Raf/MEK/ERK, the PI3K/AKT/mTOR, and the Bcl-2 pathways as potentially relevant targets for therapeutic intervention. We have previously demonstrated that constitutive ERK phosphorylation is an independent predictor of failure to achieve complete remission in adult ALL (Blood2007;109:5473) and thus we evaluated the in vitro activity of MEK-inhibitors. However, neither PD98059 nor PD0325901 affected cell growth, cell cycle distribution, and/or apoptosis in ALL cell lines (IC50 &gt;1 μM for PD0325901). These results were confirmed in primary ALL samples, in which PD98059 significantly (P=0.012) inhibited ERK phosphorylation in 8/12 samples, without inducing cell cycle changes or apoptosis. We next investigated the activity of the mTOR inhibitor Temsirolimus. Temsirolimus displayed a biphasic dose-response in a panel of different ALL cell lines, with a flat curve (35–55% of inhibition) at concentrations ranging between 1 and 5,000 nM and more pronounced growth inhibition at concentrations ≥ 10 μM. The CEM cell line was the most sensitive (IC50: 7 nM), Jurkat showed intermediate sensitivity (IC50: 200 nM), while MOLT-4 were resistant (IC50 &gt; 20,000 nM). Cell growth inhibition was associated with inhibition of cell cycle progression, while apoptosis induction was observed in less than 15% of the cells even at the highest concentration of Temsirolimus (20 μM). We then investigated the cell cycle and apoptotic effects of ABT-737 (kindly provided by Abbott Laboratories to A.T.), a Bcl-2/Bcl-xL (BH3 mimetic) inhibitor, in ALL cell lines and in 10 primary samples. ABT-737 showed a potent dose- and time-dependent growth-inhibitory activity in MOLT-4 (IC50: 198 nM), associated with loss of mitochondrial membrane potential, caspase activation, Bcl-2 cleavage, and ultimately apoptosis induction. Conversely, CEM cells proved resistant (IC50: 12,000 nM). We also found that ABT-737 was highly effective in primary adult and childhood ALL, independent of their chromosomal abnormalities, with a significant decrease in viability (p=0.008) and a remarkable induction of apoptosis (from a mean baseline value of 16.8±8.8% to 43.6±22.8%, p=0.04) at 10 nM ABT-737. A dose-dependent down-regulation of Bcl-2 and Bcl-xL expression was observed in sensitive samples, but not in the only resistant one. In summary, our study shows that ALL cells, do not undergo apoptosis in response to single-pathway inhibition, suggesting the presence of multiple, redundant pathways that preserve leukemic cell survival. The only notable exception was the Bcl-2/Bcl-xL inhibitor ABT-737. Studies are ongoing to identify mechanism-driven combinations of agents that would disrupt multiple signal transduction pathways, resulting in synergistic killing and, ultimately, in novel therapeutic strategies for ALL.

Dual Inhibition of mTOR and Pim Kinase Pathways Using Small Molecule Inhibitors Synergistically Kills Myeloid Leukemic Cells In Vitro and In Vivo.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 293-293
Author(s):  
Yingwei Lin ◽  
Amanda M Graham ◽  
Luciano J Costa ◽  
Zanna M Beharry ◽  
Michael S Rosol ◽  
...  
Keyword(s):  
Small Molecule ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Scid Mice ◽  
Leukemia Cell Line ◽  
Down Regulation ◽  
Pim Kinases ◽  
Mtorc1 Pathway

Abstract Abstract 293 The serine/threonine Pim kinases are known to play an important role in several signal transduction pathways, including those regulated by c-Myc, N-Myc, FLT3-ITD, BCR-ABL, HOXA9, and EWS fusions. Pim kinases are up regulated in some hematologic malignancies such as Acute Myeloid Leukemia (AML) and Chronic Lymphocytic Leukemia. Pim kinases were first identified as a proviral integration site in the mice that overexpress c-Myc and enhance lymphomagenesis. We have previously shown that SMI-4a, a novel benzylidene-thiazolidine-2,4-dione small molecule inhibitor of the Pim kinases inhibited the growth of precursor T-cell lymphoblastic leukemia in the mouse (Lin, YW. et al. Blood, 2010). We have also reported that SMI-4a in combination with a few MEK inhibitors or standard chemotherapeutic agents including daunorubicin, Ara-C, and 6-thioguanine synergistically killed myeloid and lymphoblastic leukemic cell lines as well as primary patient leukemic blasts (Lin, YW. et al. Blood, 2010, AACR 2010 abstract). In the current study, we found that the combination of Rapamycin and Pim kinase inhibitors including SMI-4a, SMI-20a, SMI-24a, and K00135 synergistically killed MV4-11, a myeloid leukemia cell line harboring FLT3-ITD. We also show that a combination of SMI-4a and Rapamycin significantly inhibited subcutaneous tumor growth of MV4-11 expressing firefly-luciferase in NOD/SCID mice, which was determined using conventional caliper measurement and bioluminescent analysis in the region of interest. Although the combination of those drugs caused a loss of appetite in NOD/SCID mice in the first week of the treatment, the mice became tolerable and did not lose weight from the second week. In addition, none of those drugs alone or in combination caused any adverse affects in wild type FVB mice. A combination of SMI-4a and Rapamycin also synergistically kills primary AML blasts including patients with or without expression of the FLT3-ITD. The treatment with SMI-4a or Rapamycin as a single agent down regulates phosphorylation of two substrates of the mTORC1 pathway, 4E-BP1 and S6K, while the combination significantly decreased their phosphorylation compared with single agent treatments, which is consistent with the synergistic effect. We found that SMI-4a increased phosphorylation of AMPK and decreased phosphorylation of mTOR at serine 2448 leading to down regulation of the mTORC1 pathway. In contrast, Rapamycin induced down regulation of 4E-BP1 and S6K without affecting phosphorylation of AMPK and mTOR. SMI-4a induced apoptotic cell death that was characterized by down regulation of MCL1, cleavage of Caspase 3, and nuclear condensation, whereas Rapamycin did not induce these changes. Together those two inhibitors modify different signaling pathways to synergistically kill AML blasts in vitro and in vivo. Disclosures: Tholanikunnel: Vortex Biotechnology: Employment. Kraft:Vortex Biotechnology: Consultancy.

scholarly journals Synergistic efficacy of inhibiting MYCN and mTOR signaling against neuroblastoma

BMC Cancer ◽  
2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Matthew J. Kling ◽  
Connor N. Griggs ◽  
Erin M. McIntyre ◽  
Gracey Alexander ◽  
Sutapa Ray ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Protein Synthesis ◽  
Cell Growth ◽  
Therapeutic Potential ◽  
Single Agent ◽  
Annexin V ◽  
Mtor Signaling ◽  
Mycn Amplification ◽  
Global Protein Synthesis ◽  
P70 S6k

Abstract Background Neuroblastoma (NB) patients with MYCN amplification or overexpression respond poorly to current therapies and exhibit extremely poor clinical outcomes. PI3K-mTOR signaling-driven deregulation of protein synthesis is very common in NB and various other cancers that promote MYCN stabilization. In addition, both the MYCN and mTOR signaling axes can directly regulate a common translation pathway that leads to increased protein synthesis and cell proliferation. However, a strategy of concurrently targeting MYCN and mTOR signaling in NB remains unexplored. This study aimed to investigate the therapeutic potential of targeting dysregulated protein synthesis pathways by inhibiting the MYCN and mTOR pathways together in NB. Methods Using small molecule/pharmacologic approaches, we evaluated the effects of combined inhibition of MYCN transcription and mTOR signaling on NB cell growth/survival and associated molecular mechanism(s) in NB cell lines. We used two well-established BET (bromodomain extra-terminal) protein inhibitors (JQ1, OTX-015), and a clinically relevant mTOR inhibitor, temsirolimus, to target MYCN transcription and mTOR signaling, respectively. The single agent and combined efficacies of these inhibitors on NB cell growth, apoptosis, cell cycle and neurospheres were assessed using MTT, Annexin-V, propidium-iodide staining and sphere assays, respectively. Effects of inhibitors on global protein synthesis were quantified using a fluorescence-based (FamAzide)-based protein synthesis assay. Further, we investigated the specificities of these inhibitors in targeting the associated pathways/molecules using western blot analyses. Results Co-treatment of JQ1 or OTX-015 with temsirolimus synergistically suppressed NB cell growth/survival by inducing G1 cell cycle arrest and apoptosis with greatest efficacy in MYCN-amplified NB cells. Mechanistically, the co-treatment of JQ1 or OTX-015 with temsirolimus significantly downregulated the expression levels of phosphorylated 4EBP1/p70-S6K/eIF4E (mTOR components) and BRD4 (BET protein)/MYCN proteins. Further, this combination significantly inhibited global protein synthesis, compared to single agents. Our findings also demonstrated that both JQ1 and temsirolimus chemosensitized NB cells when tested in combination with cisplatin chemotherapy. Conclusions Together, our findings demonstrate synergistic efficacy of JQ1 or OTX-015 and temsirolimus against MYCN-driven NB, by dual-inhibition of MYCN (targeting transcription) and mTOR (targeting translation). Additional preclinical evaluation is warranted to determine the clinical utility of targeted therapy for high-risk NB patients.

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