Abstract
Rearranged during transfection (RET) fusion-positive non-small cell lung cancer (NSCLC) accounts for approximately 1–2% of all NSCLCs. To date, RET fusions that involve at least six fusion partners in NSCLC, such as KIF5B, CCDC6, NCOA4, TRIM33, CLIP1, and ERC1, have been identified. 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. In the present study, we investigated the effects of alectinib on NCOA4-RET fusion-positive tumor cells in vitro and in vivo. 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. 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.
Highlights
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 [1]
We demonstrated that alectinib is effective at inhibiting native tumor cell lines harboring NCOA4-Rearranged during transfection (RET) (EHMES-10)
Alectinib treatment could rescue the pleural carcinomatosis caused by the EHMES-10 cells
Summary
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 [1]. RET is located at 10q11.2, which encodes RET receptor tyrosine kinase. This gene plays important physiological roles in neural and renal development [2]. RET fusion genes are thought to be oncogenic drivers and they are detected in 20–40% of all papillary thyroid cancers [3]. Recent clinical trials for RET fusion-positive NSCLCs using vandetanib or cabozantinib demonstrated good clinical responses [10, 13]. Vandetanib showed a response rate of 53% (9/17 cases). Vandetanib showed much higher response rates in CCDC6RET-positive NSCLCs (83% [5/6 cases]) compared to KIF5B-RET-positive NSCLCs (20% [2/10 cases]) [13]. Cabozantinib showed a response rate of 28% (7/25 cases).
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