Exosomes from Irradiated Nonsmall Cell Lung Cancer Cells Reduced Sensitivity of Recipient Cells to Anaplastic Lymphoma Kinase Inhibitors

Exosomes, released from various cell types, serve as vehicles of intercellular communication. Rearranged anaplastic lymphoma kinase (ALK) has been detected in exosomes released from cancer cells in ALK-positive nonsmall cell lung cancer (NSCLC), however, the functional consequence of ALK in exosomes has not been studied. This study aims to address whether exosomal ALK release is affected by stress, and whether exosomal ALK can modulate survival of recipient cells in vitro and in vivo. Exosomes, isolated from ALK-containing H3122 cells with (Exo-Apo) or without (Exo-Ctrl) irradiation treatment, were transferred to recipient H3122 cells in vitro or mouse xenograft in vivo. Western blot, flow cytometry, MTT, and xenograft were employed to respectively assess activation of the ALK pathway, apoptosis, cell viability, and tumor growth. Exo-Apo contained much higher levels of phosphorylated ALK (p-ALK) than that of Exo-Ctrl, and it activated AKT, STAT3, and the ERK pathway in recipient H3122 cells. ALK-specific inhibitors, including Crizotinib, Ceritinib, and TAE684, exhibited less effects on H3122 cells preincubated with Exo-Apo than on those treated with Exo-Ctrl in either inhibition of cell viability or promotion of apoptosis. Moreover, in an H3122 xenograft model, the Exo-Apo treatment resulted in a greater tumor growth and less sensitivity to Ceritinib than the Exo-Ctrl treatment. The ALK protein cargo in exosomes could be a key element to drive tumor growth and compromise therapeutic efficacy of ALK inhibitors for ALK-positive NSCLC.