byl719 and Neuroblastoma

Neuroblastoma (NB), the most frequent solid extracranial tumor in children, is not always cured by current aggressive therapies that have notable adverse effects; therefore, novel treatments are necessary. Phosphoinositide 3‑kinase (PI3K) and fibroblast growth factor receptor inhibitors exhibit synergistic effect in NB cell lines. In the present study, mono‑ and combination therapy of the United States Food and Drug Administration‑approved PI3K, cyclin‑dependent kinase‑4/6 (CDK4/6), poly‑ADP‑ribose‑polymerase (PARP) and WEE1 G2 checkpoint kinase (WEE1) inhibitors (BYL719, PD‑0332991, BMN673 and MK‑1775, respectively), were used to treat NB cell lines SK‑N‑AS, SK‑N‑BE(2)‑C, SK‑N‑DZ, SK‑N‑FI and SK‑N‑SH and viability (assessed by WST‑1 assay), proliferation (incucyte analysis) and cell cycle (FACS) changes were assessed. Treatments with all single drugs presented dose‑-dependent responses with decreased viability and proliferation and combining BYL719 with PD‑0332991 or BMN673 with MK‑1775 resulted in additive or synergistic effects in most cell lines., except for SK‑N‑SH for the former and for SK‑N‑AS for the latter. Moreover, combining MK‑1775 and BMN673 decreased the numbers of cells in S phase to a greater extent than either drug alone, while when combining PD‑0332991 and BYL719 the observed effect was close to that of PD‑0332991 alone. To summarize, PI3K and CDK4/6 or PARP and WEE1 exhibited synergistic anti‑NB effects and lower doses of the inhibitors could be utilized, thereby potentially reducing adverse side effects.

Topics: Cell Cycle Proteins; Cell Line, Tumor; Cell Proliferation; Child; Cyclin-Dependent Kinase 4; Humans; Neuroblastoma; Phosphatidylinositol 3-Kinase; Phosphatidylinositol 3-Kinases; Poly(ADP-ribose) Polymerase Inhibitors; Protein-Tyrosine Kinases

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.

Topics: Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Proliferation; Cell Survival; Child; Cisplatin; Cytostatic Agents; Doxorubicin; Drug Resistance, Neoplasm; Drug Synergism; Humans; Neuroblastoma; Phosphoinositide-3 Kinase Inhibitors; Pyrazoles; Quinoxalines; Receptors, Fibroblast Growth Factor; Thiazoles; Vincristine