Abstract 856: Combination of crizotinib and radiation in the treatment of ALK-positive and cetuximab-resistant lung cancer

We examined the effect of crizotinib in combination with radiation on ALK signaling, cell proliferation, cell cycle distribution and radiosensitivity in ALK-positive NSCLC cell lines H3122 and H2228 in vitro. We also examined the in-vivo effects of crizotinib in combination with radiation in H3122 and H2228 xenograft models. Crizotinib blocked phosphorylation of ALK and its downstream effectors and inhibited cell proliferation in a dose-dependent manner. The combination of crizotinib and radiation resulted in increased inhibition of cell growth. Although cells were sensitized to radiation by crizotinib, molecular knockdown of ALK by siRNA had only modest impact on cell radiosensitivity. Cell cycle analysis by flow cytometry showed that ALK-siRNA induced G1 arrest. Interestingly, low dose crizotinib induced G1 arrest, while doses above 2µM induced G2 arrest. Combination treatment induced arrest in G1 and G2 phases and decreased the cell population in S-phase. Moreover, in xenograft tumor models, we observed combined treatment to produce additive tumor growth inhibition over that observed with either drug or radiation alone. We further examined the capacity of crizotinib overcome cetuximab resistance in our established in vitro resistance models. Compared with parental cells, cetuximab-resistant cells showed cross-resistance to radiation. Crizotinib inhibited the growth of cetuximab-resistant cells and resensitized cells to radiation. Compared with single-agent treatment, the ...
Source: Cancer Research - Category: Cancer & Oncology Authors: Tags: Clinical Research (Excluding Clinical Trials) Source Type: research