Mechanism of HSP90 Inhibitor AUY-922 Reversing ALK Inhibitor Resistance in Human Neuroblastoma Cells

Objective To investigate the mechanism of HSP90 inhibitor AUY-922 reversing the resistance of human neuroblastoma cells to the second generation ALK inhibitor TAE684.

Methods The effect of AUY-922 on the proliferation of human neuroblastoma cells SH-SY5Y and KELLY carrying ALK F1174L gene was detected by MTT method. The effect of AUY-922 on cell cycle of SH-SY5Y and KELLY cells was detected by flow cytometry. The effects of AUY-922 on cyclin Cdc2, ALK protein and downstream signal pathways p-Akt, p-Erk, p-stat3 in SH-SY5Y and KELLY cells were detected by Western blot.

Results AUY-922 could significantly inhibit the proliferation of SH-SY5Y and KELLY cells, and the IC₅₀ were about 0.30 μmol/L and 0.12 μmol/L, respectively. AUY-922 could induce cell cycle arrest of SH-SY5Y and KELLY cells in G₂/M phase in a dose-dependent manner. AUY-922 could degrade Cdc2 and ALK proteins in SH-SY5Y and KELLY cells in a dose-dependent manner, and reduce the levels of p-Akt, p-Erk and p-stat3.

Conclusion The reversal effect of HSP90 inhibitor AUY-922 on drug resistance of human neuroblastoma to ALK inhibitor may be related to its induction of G₂/M cell cycle arrest, the degradation of ALK protein and the inhibition of downstream signal pathway.