Format

Send to

Choose Destination
Clin Cancer Res. 2018 Sep 1;24(17):4162-4174. doi: 10.1158/1078-0432.CCR-17-3492. Epub 2018 May 18.

Integrin β3 Inhibition Enhances the Antitumor Activity of ALK Inhibitor in ALK-Rearranged NSCLC.

Noh KW1,2, Sohn I3, Song JY2, Shin HT1, Kim YJ2, Jung K1,2, Sung M2, Kim M1,2, An S1,2, Han J4, Lee SH1,5, Lee MS6,2, Choi YL6,2,4.

Author information

1
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea.
2
Lab of Cancer Genomics and Molecular Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
3
Statistics and Data Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul, Korea.
4
Department of Pathology and Translational Genomics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
5
Division of Hematology-Oncology, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
6
Department of Health Sciences and Technology, SAIHST, Sungkyunkwan University, Seoul, Korea. ylachoi@skku.edu misook98@gmail.com.

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.

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center