mTOR ATP-competitive inhibitor INK128 inhibits neuroblastoma growth via blocking mTORC signaling

Area of Science:

• Oncology
• Molecular Biology
• Pharmacology

Background:

• High-risk neuroblastoma frequently exhibits resistance to conventional high-dose chemotherapy.
• The mechanistic target of rapamycin (mTOR) signaling pathway is often dysregulated in various human cancers.
• Targeting mTOR signaling has shown promise in sensitizing diverse cancer types to chemotherapy.

Purpose of the Study:

• To investigate the efficacy of the mTOR inhibitor INK128 in neuroblastoma models.
• To determine if INK128 can enhance the effects of doxorubicin (Dox) in neuroblastoma.
• To explore INK128's potential to overcome chemotherapy resistance in neuroblastoma.

Main Methods:

• Utilized a panel of neuroblastoma cell lines for in vitro studies.
• Assessed the effects of INK128 on anchorage-dependent and independent cell growth.
• Evaluated INK128's impact on doxorubicin (Dox) cytotoxicity and apoptosis induction.
• Employed an orthotopic neuroblastoma mouse model for in vivo efficacy assessment.

Main Results:

• INK128 demonstrated significant inhibition of neuroblastoma cell growth in vitro.
• INK128 markedly enhanced the cytotoxic effects of doxorubicin (Dox) on neuroblastoma cells.
• INK128 treatment blocked downstream mTOR signaling activation and boosted Dox-induced apoptosis.
• INK128 successfully overcame established chemoresistance in the LA-N-6 neuroblastoma cell line.
• In vivo studies showed that INK128 significantly inhibited tumor growth in an orthotopic mouse model.

Conclusions:

• INK128-mediated mTOR inhibition exhibits substantial antitumor activity against neuroblastoma.
• INK128 significantly increases the sensitivity of neuroblastoma cells to doxorubicin (Dox) therapy.
• INK128 represents a promising therapeutic agent for enhancing current chemotherapeutic regimens and restoring drug sensitivity in neuroblastoma.