Figure 3. Combination of ceritinib with CGM097 leads to increased antitumor activity in TP53 wild-type neuroblastoma xenograft tumors harboring ALK aberrations.

(A) The improved in vivo efficacy in the NB-1, SH-SY5Y and NB-1643 xenograft mouse models that harbor wild-type TP53 and ALK aberrations when ceritinib was combined with CGM097 and lack of antitumor activity of this combination in the IMR-32 xenograft tumors that harbor wild-type TP53 and ALK. The neuroblastoma cell lines NB-1, SH-SY5Y and IMR-32 were implanted into the flanks of nude mice and NB-1643 in SCID mice. Animals were randomized into four groups when the average tumor volume was 200–300 mm³ and received vehicle, ceritinib (50 mg/kg), CGM097 (50 mg/kg) or both inhibitors in combination. Combination of ceritinib with CGM097 was withdrawn on day 60 and day 45 for NB-1 and SH-SY5Y, respectively, to allow tumor regrowth. Tumor dimensions and body weights were measured at the time of randomization and twice weekly thereafter for the study duration. Average tumor volume and SEM are shown as a function of time. (B) Inhibition of phospho-ALK, induction of p21 and increased levels of cleaved PARP in NB-1, SH-SY5Y and NB-1643 xenograft tissues treated with ceritinib in combination with CGM097. Animals were treated with vehicle, ceritinib (50 mg/kg), CGM097 (50 mg/kg) or both inhibitors in combination for 3 days. Tumor tissues were recovered 4 hr after the last dose treatment and analyzed by Western blotting.

DOI: http://dx.doi.org/10.7554/eLife.17137.005