Efficacy of combined targeted therapy with PI3K and CDK4/6 or PARP and WEE1 inhibitors in neuroblastoma cell lines

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.