1. Effects of PI3K and FGFR inhibitors alone and in combination, and with/without cytostatics in childhood neuroblastoma cell lines.
- Author
-
Holzhauser S, Lukoseviciute M, Papachristofi C, Vasilopoulou C, Herold N, Wickström M, Kostopoulou ON, and Dalianis T
- Subjects
- Antineoplastic Combined Chemotherapy Protocols therapeutic use, Apoptosis drug effects, Cell Line, Tumor, Cell Proliferation drug effects, Cell Survival drug effects, Child, Cisplatin pharmacology, Cisplatin therapeutic use, Cytostatic Agents therapeutic use, Doxorubicin pharmacology, Doxorubicin therapeutic use, Drug Resistance, Neoplasm, Drug Synergism, Humans, Neuroblastoma pathology, Phosphoinositide-3 Kinase Inhibitors therapeutic use, Pyrazoles pharmacology, Pyrazoles therapeutic use, Quinoxalines pharmacology, Quinoxalines therapeutic use, Receptors, Fibroblast Growth Factor metabolism, Thiazoles pharmacology, Thiazoles therapeutic use, Vincristine pharmacology, Vincristine therapeutic use, Antineoplastic Combined Chemotherapy Protocols pharmacology, Cytostatic Agents pharmacology, Neuroblastoma drug therapy, Phosphoinositide-3 Kinase Inhibitors pharmacology, Receptors, Fibroblast Growth Factor antagonists & inhibitors
- Abstract
Neuroblastoma (NB) is a heterogenous disease with treatment varying from observation for low‑risk tumors, to extensive therapy with chemotherapy, surgery, radiotherapy, and autologous bone‑marrow‑transplantation and immunotherapy. However, a high frequency of primary‑chemo‑refractory disease and recurrences urgently require novel treatment strategies. The present study therefore investigated the anti‑NB efficacy of the recently FDA‑approved phosphoinositide 3‑kinase (PI3K) and fibroblast growth factor receptor (FGFR) inhibitors, alpelisib (BYL719) and erdafitinib (JNJ‑42756493), alone and in combination with or without cisplatin, vincristine, or doxorubicin on 5 NB cell lines. For this purpose, the NB cell lines, SK‑N‑AS, SK‑N‑BE(2)‑C, SK‑N‑DZ, SK‑N‑FI and SK‑N‑SH (where SK‑N‑DZ had a deletion of PIK3C2G and none had FGFR mutations according to the Cancer Program's Dependency Map, although some were chemoresistant), were tested for their sensitivity to FDA‑approved inhibitors alone or in combination, or together with cytostatic drugs by viability, cytotoxicity, apoptosis and proliferation assays. The results revealed that monotherapy with alpelisib or erdafitinib resulted in a dose‑dependent inhibition of cell viability and proliferation. Notably, the combined use of PI3K and FGFR inhibitors resulted in an enhanced efficacy, while their combined use with the canonical cytotoxic agents, cisplatin, vincristine and doxorubicin, resulted in variable synergistic, additive and antagonistic effects. Collectively, the present study provides pre‑clinical evidence that PI3K and FGFR inhibitors exhibit promising anti‑NB activity. The data presented herein also indicate that the incorporation of these inhibitors into chemotherapeutic regimens requires careful consideration and further research in order to obtain a beneficial efficacy. Nevertheless, the addition of PI3K and FGFR inhibitors to the treatment arsenal might reduce the occurrence of refractory and relapsing disease in NB without FGFR and PI3K mutations.
- Published
- 2021
- Full Text
- View/download PDF