Targeting the mTOR Complex by Everolimus in NRAS Mutant Neuroblastoma

Abstract

High-risk neuroblastoma remains lethal in about 50% of patients despite multimodal treatment. Recent attempts to identify molecular targets for specific therapies have shown that Neuroblastoma RAS (NRAS) is significantly mutated in a small number of patients. However, few inhibitors for the potential treatment for NRAS mutant neuroblastoma have been investigated so far. In this in-vitro study, we show that MEK inhibitors AZD6244, MEK162 and PD0325901 block cell growth in NRAS mutant neuroblastoma cell lines but not in NRAS wild-type cell lines. Several studies show that mutant NRAS leads to PI3K pathway activation and combined inhibitors of PI3K/mTOR effectively block cell growth. However, we observed the combination of MEK inhibitors with PI3K or AKT inhibitors did not show synergestic effects on cell growth. Thus, we tested single mTOR inhibitors Everolimus and AZD8055. Interestingly, Everolimus and AZD8055 alone were sufficient to block cell growth in NRAS mutant cell lines but not in wild-type cell lines. We found that Everolimus alone induced apoptosis in NRAS mutant neuroblastoma. Furthermore, the combination of mTOR and MEK inhibitors resulted in synergistic growth inhibition. Taken together, our results show that NRAS mutant neuroblastoma can be targeted by clinically available Everolimus alone or in combination with MEK inhibitors which could impact future clinical studies.

A Phase I Study of the CDK4/6 Inhibitor Ribociclib (LEE011) in Pediatric Patients with Malignant Rhabdoid Tumors, Neuroblastoma, and Other Solid Tumors

“…Further studies of ribociclib in combination with other active agents in patients with MRT and neuroblastoma are ongoing, such as the AcS e-ESMART multi-arm trial (NCT02813135), which includes ribociclib in combination with everolimus (a PI3K/ AKT/mTOR pathway inhibitor) or chemotherapy in patients prescreened for specific molecular alterations. The combination with everolimus was based on the observation that the PI3K/AKT/ mTOR pathway, for example, via MYCN, ALK, or RAS activation, may be implicated in the pathogenesis of neuroblastoma and MRT (30,31). Other ribociclib-based combinations with other targeted therapies, such as MAPK/ERK inhibitors, may be considered in future trials.…”

Irinotecan–temozolomide with temsirolimus or dinutuximab in children with refractory or relapsed neuroblastoma (COG ANBL1221): an open-label, randomised, phase 2 trial

“…(5, 6) Although single agent activity was modest in some preclinical studies,(7, 8) data suggest that mTOR inhibitors may be effective in subsets of neuroblastoma tumours. (9) In addition, mTOR inhibitors have synergistic or additive effects when combined with chemotherapeutics. (10, 11) Previous studies provided temsirolimus dosing information,(12, 13) and a COG trial demonstrated that I/T/TEM could be delivered safely to children with relapsed/refractory solid tumours.…”

Treatment of relapse/progression of the disease in patients with neuroblastoma in the Republic of Belarus over a 20-year period: a cohort study

“…Необходимо продолжить изучение биологии опухоли и на основании этого индивидуализировать подход к лечению. Возможно использование различных видов таргетных препаратов [23][24][25] и иммунотерапии (различных опухолеспецифических антител, CAR-T-клеток, ДНК и белковых вакцин) станет лучшим видом лечения для данной категории пациентов [26,27]. Проведение исследований в этой области требует объединения усилий специалистов разных стран и исследовательских центров.…”