Integrin β3 Inhibition Enhances the Antitumor Activity of ALK Inhibitor in <i>ALK</i>-Rearranged NSCLC.

Abstract

<b>Purpose:</b> Anaplastic lymphoma kinase (<i>ALK)</i>-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.<b>Experimental Design:</b> We screened <i>ALK</i>-rearranged non-small cell lung cancer (NSCLC) cases using immunohistochemistry and fluorescence <i>in situ</i> 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 <i>in vivo</i> lung cancer model studies were performed.<b>Results:</b> Among patients with <i>ALK</i>-rearranged NSCLC, integrin β3 (<i>ITGB3</i>) was one of the overexpressed genes in comparison with that in ALK-negative NSCLC (<i>P</i> = 0.0003). ALK and integrin β3 expression were positively correlated, and we discovered that high integrin β3 mRNA expression was associated with metastasis and more advanced tumor stages (<i>P</i> < 0.005; <i>P</i> < 0.05). Furthermore, we found that inhibition of both ALK and integrin β3 led to increased drug sensitivity <i>in vitro</i> and <i>in vivo</i> (both <i>P</i> < 0.05).<b>Conclusions:</b> We discovered a positive correlation between ALK and integrin β3 expression levels in <i>ALK</i>-rearranged NSCLC. Our findings suggest that high integrin β3 expression in <i>ALK</i>-rearranged NSCLC is associated with tumor progression and a worse prognosis. This finding demonstrates the prognostic value of integrin β3 and provides a rationale for combination treatment with ALK and integrin β3 inhibitors in patients with <i>ALK</i>-rearranged NSCLC. <i>Clin Cancer Res; 24(17); 4162-74. ©2018 AACR</i>.