NCOA4-RET fusion in colorectal cancer: Therapeutic challenge using patient-derived tumor cell lines

Abstract

The RET fusion is considered as the potential novel target in solid tumors. However, RET fusion is not well yet identified in colorectal cancer (CRC), and the effect of RET kinase inhibitor is also not evaluated in CRC with RET fusion. We established patient-derived tumor cells (PDCs) with RET fusion from recurrent brain metastatic lesion that newly appeared during the surveillance for stage III CRC patient. To investigate therapeutic options to CRC patient with a RET fusion, we performed cell viability assays using the PDCs. NCOA4-RET fusion was detected by FusionPlex using the resected brain metastatic tissue of CRC patient with solitary brain metastasis and then reconfirmed by fluorescence in situ hybridization (FISH) test. We also confirmed the RET fusions by a qPCR in matched PDCs. We tested whether the PDCs from RET fusion colon cancer were sensitive to carbozantinib, sorafenib, vandetanib, and PD0331992. Cell viability assays showed that carbozantinib, sorafenib, and PD0332991 did not suppress cell viability. Only, vandetanib revealed the significant inhibitory effect in MTT proliferation assay. Next, we analyzed regulation of targeted downstream pathways upon exposure to vandetanib by immunoblot assay. In colon cancer PDCs with NCOA4-RET fusion, vandetanib potently inhibited AKT and ERK phosphorylation. This study shows that vandetanib might be one of useful treatment strategies for CRC patient with NCOA4-RET fusion. Therefore, inhibition of the RET kinase is a promising targeted therapy for cancer patients whose tumors harbor a RET rearrangement.

Keywords: Colorectal cancer; RET fusion; vandetanib.

Figure 1

Single brain mass in magnetic resonance imaging (MRI)

Figure 2

Fluorescence in situ hybridization (FISH) test.

Figure 3

Confirmation of the RET fusions by a qPCR in matched PDCs (a) and (b).

Figure 4

A cell viability assay in patient-derived tumor cells (PDCs) with RET fusion (a) and targeted downstream pathways upon exposure to vandetanib by immunoblot assay (b).