Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma

Abstract

The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM). Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency. Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures and in multiple xenograft models ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3β at serine 9. GSK3β promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells and Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction and These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies..

ONC201 and imipridones: Anti-cancer compounds with clinical efficacy

“…Furthermore, disruption of mitochondrial function (e.g. OXPHOS) in tumor cells has been recently reported for ONC201, which may be explained by ClpP agonism [29] , [30] . Whether ClpP expression or activity ultimately is sufficient to predict ONC201 sensitivity in humans remains under investigation.…”

Targeting Mitochondria in Melanoma

“…ONC212 is reported to inhibit mitochondrial respiration in glioblastoma and breast cancer [ 42 , 43 ]. ONC212-treatment of melanoma cells (A375, WM47, and WM3000) led to 58% to 78% reductions in basal OCR and 55% to 89% lower ATP-R. Interestingly, basal OCR and ATP-R showed no sensitivity to ONC212 in WM3311 cells ( Figure 4 c,d,f).…”

“…ONC212, another analogue of this family, displays enhanced anti-tumor effects in comparison with ONC201 [ 41 ]. Recently, ONC201 and ONC212 have been shown to reduce mitochondrial respiration in breast cancer, glioblastoma and lymphoma [ 42 , 43 , 44 ]. In agreement with these studies, we observed that ONC212 lowered mitochondrial respiration, including basal respiration, ATP-R and MAXR independent of the BRAF or NRAS mutation status.…”

“…Remarkably, they had no effects on non-cancerous cells [ 39 , 40 , 41 ]. Recently, suppression of mitochondrial respiration has been reported as a novel mechanism of action of imipridone agents in glioblastoma and breast cancer [ 42 , 43 , 44 ].…”

Xanthohumol suppresses glioblastoma via modulation of Hexokinase 2 -mediated glycolysis

“…Recently studies have demonstrated that deregulation of glycolysis confers several tumorigenic advantages to GBMs, including facilitation of proliferation, migration, and invasion. Consequently, the accumulation of lactate forms a specific microenvironmental condition to promote tumor cell invasion and metastasis [35][36][37][38][39]. The glycolytic enzymes, including the glucose transporter 1 (Glut1), HK2 and pyruvate kinase 2 (PKM2), are deregulated in human GBM cells and play exclusive effect in the tumorigenesis of GBM [36,[40][41][42].…”