1708P - Anti-tumor activity of alectinib in the orthotopic in vivo imaging model with NCOA4-RET fusion positive tumor cells

Date 11 September 2017
Event ESMO 2017 Congress
Session Poster display session
Topics Drug Development
Biomarkers
Presenter Seiji Yano
Citation Annals of Oncology (2017) 28 (suppl_5): v595-v604. 10.1093/annonc/mdx391
Authors S. Yano, S. Arai, K. Kita, A. Tanimoto, S. Takeuchi
  • Division Of Medical Oncology, Kanazawa University, 920-0934 - Kanazawa/JP

Abstract

Background

The rearranged during transfection (RET) gene was discovered in 1985 as an oncogene produced by recombination during the transfection of NIH 3T3 cells with human lymphoma DNA. RET fusion genes were recently identified in a population of non-small cell lung cancers (NSCLCs). The most common (>80%) fusion partner for RET is KIF5B, followed by CCDC6, NCOA4, TRIM33, CLIP1, and ERC1. Recent clinical trials for RET fusion-positive NSCLC using vandetanib or cabozantinib demonstrated positive clinical response and considerable differential activities for RET inhibitors among fusion partners. Alectinib, an approved ALK inhibitor, is reported to inhibit KIF5B-RET and CCDC6-RET. However, the activity of alectinib with respect to RET with other fusion partners is unknown.

Methods

In the present study, we investigated the effects of alectinib on NCOA4-RET fusion-positive tumor cells (EHMES-10, a mesothelioma cell line) in vitro by MTT assay. We also examined the effect of alectinib utilizing orthotopic implantation model with EHMES-10 cells in the in vivo imaging model.

Results

Alectinib inhibited the viability of NCOA4-RET-positive EHMES-10 cells, as well as CCDC6-RET-positive LC-2/ad and TPC-1 cells. This was achieved via inhibition of the phosphorylation of RET and induction of apoptosis. Moreover, alectinib suppressed the production of thoracic tumors and pleural effusions in an orthotopic intrathoracic inoculation model of EHMES-10 cells. In vivo imaging of an orthotopically inoculated EHMES-10 cell model also revealed that alectinib could rescue pleural carcinomatosis.

Conclusions

These results suggest that alectinib may be a promising RET inhibitor against tumors positive for not only KIF5B-RET and CCDC6-RET, but also NCOA4-RET.

Clinical trial identification

Legal entity responsible for the study

Kanazawa University

Funding

AMED in Japan

Disclosure

S. Yano: Research grants and honoraria from Chugai Pharma. All other authors have declared no conflicts of interest.