The MDM2 inhibitor CGM097 combined with the BET inhibitor OTX015 induces cell death and inhibits tumor growth in models of neuroblastoma

Abstract

Background Neuroblastoma (NB) is the most common extracranial solid tumor in infants and children, with amplification of the oncogene MYCN being a hallmark of high‐risk disease and poor prognosis. Although less frequent, overexpression of MYC is similarly an indicator of poor prognosis. Most NB tumors initially respond to chemotherapy, however, most will relapse, resulting in chemoresistant disease. After relapse, there is growing evidence of p53 inactivation. MYC/MYCN and MDM2 have been shown to interact and contribute to NB growth and disease progression. MDM2 inhibitors and Bromodomain and Extra‐Terminal domain (BET) inhibitors have both shown promise in treating NB by increasing the expression of p53 and decreasing MYC/MYCN expression, respectively. Our study focuses on the combined treatment of a MDM2 inhibitor (CGM097) with a BET inhibitor (OTX015) in neuroblastoma. Methods Two p53 wild‐type and two p53 mutant established neuroblastoma cells lines were used to test this combination. Ray design assays were used to test whether this combination was synergistically cytotoxic to NB cells. Western blots were performed to check signaling pathways of interest after drug treatment. IncuCyte imaging and flow cytometry were utilized to quantify the apoptotic and cytostatic effects of these drugs on NB cells. In vivo studies were carried out to test the antitumor effect of this combination in a living host. Results The combination of CGM097 and OTX015 resulted in p53 activation, decreased expression of MYC family proteins and a subsequent synergistic increase in NB cell death. Conclusion This study warrants further investigation into the combination of MDM2 inhibitors and BET inhibitors for the treatment in NB.

Targeting p53 pathways: mechanisms, structures, and advances in therapy

“… 359 When combined with BET or Cdk4/6 inhibitors, NVP-CGM097 induces cell death in neuroblastoma or ER-positive breast cancer cells. 360 , 361 …”

The role of distinct BRD4 isoforms and their contribution to high-grade serous ovarian carcinoma pathogenesis

“…Combination therapy with BETi can be also very effective in overcoming chemoresistance in pre-clinical settings [ 72 , 112 , 115 , 116 ]. JQ1, for example, effectively increases sensitivity to cisplatin of platinum-resistant ovarian cancer cell line in vitro [ 72 ].…”

MDM2 Inhibition in the Treatment of Glioblastoma: From Concept to Clinical Investigation

“…Interestingly, CGM097 was found to inhibit ABCB1-associated ATPase in an in vitro study [85], which suggests the potential of this drug to counteract multi-drug resistance in conjunction with chemotherapeutic drugs to improve anti-tumor responses. The synergistic and additive effects of CGM097 have been reported in combination with the BET inhibitor OTX015 and the antimetabolite 5-fluorouracil in neuroblastoma and neuroendocrine tumor cell lines, respectively [86,87]. CGM097 significantly prolonged survival in patient-derived xenograft rodent models of B-cell acute lymphoblastic leukemia and solid tumors with functional p53 [84,88].…”