Abstract
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 β3 (ITGB3) was one of the overexpressed genes in comparison with that in ALK-negative NSCLC (P = 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 (P < 0.005; P < 0.05). Furthermore, we found that inhibition of both ALK and integrin β3 led to increased drug sensitivity in vitro and in vivo (both P < 0.05).Conclusions: We discovered a positive correlation between ALK and integrin β3 expression levels in ALK-rearranged NSCLC. Our findings suggest that high integrin β3 expression in ALK-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 ALK-rearranged NSCLC. Clin Cancer Res; 24(17); 4162-74. ©2018 AACR.
Highlights
Anaplastic lymphoma kinase (ALK)-rearranged non–small cell lung cancer (NSCLC) behaves more aggressively than other NSCLCs, showing early metastasis and an advanced stage at the time of diagnosis [1,2,3]
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)
We found that inhibition of both ALK and integrin b3 led to increased drug sensitivity in vitro and in vivo
Summary
Anaplastic lymphoma kinase (ALK)-rearranged non–small cell lung cancer (NSCLC) behaves more aggressively than other NSCLCs, showing early metastasis and an advanced stage at the time of diagnosis [1,2,3]. Patients who have advanced ALK-positive NSCLC are highly responsive to the ALK inhibitor crizotinib (Xalkori, Pfizer), with an objective response rate (ORR) of approximately 60% and a median PFS of 8 to 10 months [5]. Because of their benefits over other therapies, ALK tyrosine kinase inhibitors (ALK TKI) are used as the chemotherapeutic agents of choice in NSCLC with ALK rearrangement [6]. Treatments that add therapeutic targets, such as IGF-1R or PD-L1 along with ALK, was shown to improve responses through a synergistic or additive effect in patients with ALK-rearranged NSCLC [12,13,14]
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