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

Abstract

High-risk neuroblastoma often develops resistance to high-dose chemotherapy. The mTOR signaling cascade is frequently deregulated in human cancers and targeting mTOR signaling sensitizes many cancer types to chemotherapy. Here, using a panel of neuroblastoma cell lines, we found that the mTOR inhibitor INK128 showed inhibitory effects on both anchorage-dependent and independent growth of neuroblastoma cells and significantly enhanced the cytotoxic effects of doxorubicin (Dox) on these cell lines. Treatment of neuroblastoma cells with INK128 blocked the activation of downstream mTOR signaling and enhanced Dox-induced apoptosis. Moreover, INK128 was able to overcome the established chemoresistance in the LA-N-6 cell line. Using an orthotopic neuroblastoma mouse model, we found that INK128 significantly inhibited tumor growth in vivo. In conclusion, we have shown that INK128-mediated mTOR inhibition possessed substantial antitumor activity and could significantly increase the sensitivity of neuroblastoma cells to Doxorubicin therapy. Taken together, our results indicate that using INK128 can provide additional efficacy to current chemotherapeutic regimens and represent a new paradigm in restoring drug sensitivity in neuroblastoma.

Dual Abrogation of Mnk and Mtor: A Novel Therapeutic Approach for the Treatment of Aggressive Cancers

“…mTORC1 also has a prominent role in lipid synthesis, required for the generation of cellular membrane during proliferation [67]. Cancer cells often hijack the PI3K/AKT/mTOR pathway in order to meet the demands of increased growth rate, as observed in patients with acute myeloid leukemia [69][70][71].…”

“…Activated mTORC1 increases the transcription and translation of hypoxia inducible factor (HIF1α), which in turn regulates glycolytic genes, enabling the tumor cell to meet the high demands required for survival and progression [70,84]. There is also evidence that both mTORC1 and mTORC2 are implicated in the epithelial-mesenchymal transition (EMT) [85].…”

Heightening Energetic Stress Selectively Targets LKB1-Deficient Non–Small Cell Lung Cancers

“…These data suggested the need to evaluate next generation mTOR catalytic kinase inhibitors to target LKB1-deficient lung tumors. MLN0128 is a potent mTOR catalytic kinase inhibitor that has shown efficacy as an anti-cancer agent in cell culture and xenograft models of sarcoma, neuroblastoma and pancreatic cancer(14),(15,16) as well as GEMMs of Pten−/− prostate cancer and Myc driven lymphoma(17,18). MLN0128 is currently in clinical trials for treatment of advanced solid tumors and hematological malignancies (NCT01351350; NCT01118689).…”

Catalytic mammalian target of rapamycin inhibitors as antineoplastic agents

“…INK128 treatment significantly reduced 4E-PB1 phosphorylation in myc-driven MM and lymphoma cell lines, providing a rationale for use of this agent in these malignancies as well [67]. Apart from hematologic malignancies, there is strong evidence of INK128 activity in cell lines and xenograft models from several tumors, underscoring the potential importance of this agent in clinical oncology [68][69][70][71][72][73]. Preliminary results are available from a phase I dose escalation study of INK128 in patients with relapsed/refractory MM, Waldenström macroglobulinemia (WM) and non-Hodgkin lymphoma [74].…”