Enhancing targeted therapy by combining PI3K and AKT inhibitors with or without cisplatin or vincristine in medulloblastoma cell lines in vitro.

AIM: Despite current intensive therapy, survival rates of medulloblastoma (MB) greatly vary according to molecular subgroup, so new therapies are needed. Recently, we showed that combining phosphoinositide 3-kinase (PI3K), fibroblast growth factor receptor and cyclin-dependent-kinase-4/6 inhibitors (BYL719, JNJ-42756493 and PD-0332991, respectively) or poly (ADP-ribose) polymerase (PARP) and WEE-1 inhibitors (BMN673 and MK1775 respectively) had synergistic effects on MB. Here, in continuation, we investigated the effects of single and combined administrations of PI3K and AKT inhibitors, with/without cisplatin or vincristine on adherent or suspension cultures of different MB subgroups as well as in a spheroid culture of one MB line. MATERIAL AND METHODS: MB cell lines DAOY, UW228-3, D425, Med8A, and D283 were treated with single and combined administrations of BYL719, AZD5363, cisplatin or vincristine and followed for viability, cell confluence, cytotoxicity, and cell migration. DAOY was also tested as a spheroid culture. KEY FINDINGS: Single BYL719, AZD5363, cisplatin, or vincristine administrations gave dose-dependent responses with regard to inhibition of viability and cell confluence. Combining AZD5363 with BYL719, cisplatin or vincristine resulted in synergistic effects with regard to inhibition of viability in all cell lines, and confluence and migration in all tested cell lines. The administration of single and combined treatments to DAOY spheroids produced largely similar effects. SIGNIFICANCE: This study provides pre-clinical evidence that AKT inhibitors combined with PI3K inhibitors, cisplatin, or vincristine exhibit additive/synergistic anti-MB activity, and lower doses could be used. The latter also applied to one MB line grown as spheroids, further supporting their future potential use.

Combined targeted therapy with PI3K and CDK4/6, or FGFR inhibitors show synergistic effects in a neuroblastoma spheroid culture model.

AIM: Neuroblastoma (NB) is, in spite of current intensive therapy with severe side effects, still not cured so new therapies are needed. Recently, we showed combining phosphoinositide 3-kinase (PI3K) (BYL719), fibroblast growth factor receptor (FGFR) (JNJ-42756493) and cyclin-dependent kinase 4/6 (CDK4/6) (PD-0332991) inhibitors, in vitro in NB cell lines grown as monolayers had synergistic effects. However, there were variations depending on the combinations used and the targeted NB cell lines. To obtain further information and to mimic more natural circumstances, we investigated the effects of single and combined administrations of the above inhibitors in spheroid NB-cultures. MATERIAL AND METHODS: Spheroid cultures of NB cell lines SK-N-AS, SK-N-BE(2)-C, SK-N-FI and SK-N-SH were established and treated with single and combined administrations of BYL719, JNJ-42756493, and PD-0332991 and followed for growth, viability, proliferation, cytotoxicity and migration. KEY FINDINGS: Single inhibitor administrations gave dose dependent responses with regard to growth and viability and their combinations were efficient and resulted in a range of additive and synergistic effects. The responses to individual drugs and their various combinations were predominantly alike regardless of whether the cells were cultivated in monolayer or D spheroid NB models. However, in general, slightly higher drug concentrations were necessary in spheroidcultures. SIGNIFICANCE: This study provides pre-clinical evidence that single PI3K, FGFR, and CDK4/6, inhibitors exhibit promising anti-NB activity and when combined lower doses of the drugs could be also used in spheroid NB-cultures, supporting the pursuit of further in vitro and in vivo studies in preparation for future potential clinical use.