Integrin B3 inhibition enhances the antitumor activity of ALK inhibitor in ALK-rearranged NSCLC

Purpose: Anaplastic lymphoma kinase (ALK)-positive cancers are sensitive to small-molecule ALK kinase inhibitors, but most cases experience failure following treatment. Hence, additional drug targets and combination therapeutic treatments are needed. We investigated gene expression that is regulated by the expression of ALK and explored its roles in cancer progression and therapeutic implication. Experimental Design: We screened ALK-rearranged non–small cell lung cancer (NSCLC) cases using immunohistochemistry and fluorescence in situ hybridization and then conducted multiplex gene expression analysis. We also performed a clinicopathologic analysis to validate the findings. Additional cellular experiments, including inhibition and migration assays, and in vivo lung cancer model studies were performed. Results: Among patients with ALK-rearranged NSCLC, integrin b3 (ITGB3) was one of the overexpressed genes in comparison with that in ALK-negative NSCLC (P ¼ 0.0003). ALK and integrin b3 expression were positively correlated, and we discovered that high integrin b3 mRNA expression was associated with metastasis and more advanced tumor stages (P < 0.005; P < 0.05). Furthermore, we found that inhibition of both ALK and integrin b3 led to increased drug sensitivity in vitro and in vivo (both P < 0.05). Conclusions: We discovered a positive correlation between ALK and integrin b3 expression levels in ALK-rearranged NSCLC. Our findings suggest that high integrin b3 expression in ALK-rearranged NSCLC is associated with tumor progression and a worse prognosis.