RESUMEN
PURPOSE: Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes. MATERIALS AND METHODS: The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined. RESULTS: CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors. CONCLUSION: EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.
Asunto(s)
Humanos , Adenocarcinoma/tratamiento farmacológico , Línea Celular Tumoral , Cetuximab/farmacología , Resistencia a Antineoplásicos/efectos de los fármacos , Factor de Crecimiento Epidérmico/metabolismo , Reordenamiento Génico , Factor de Crecimiento de Hepatocito/farmacología , Indoles/farmacología , Neoplasias Pulmonares/tratamiento farmacológico , Sistema de Señalización de MAP Quinasas , Mutación , Niacinamida/análogos & derivados , Compuestos de Fenilurea/farmacología , Piperidinas/farmacología , Inhibidores de Proteínas Quinasas/uso terapéutico , Proteínas Proto-Oncogénicas c-ret/antagonistas & inhibidores , Pirroles/farmacología , Quinazolinas/farmacología , ARN Interferente Pequeño/farmacología , Receptores ErbB/genética , Transducción de Señal/efectos de los fármacos , Tirosina Quinasa 3 Similar a fms/metabolismoRESUMEN
Multiple endocrine neoplasia (MEN) type 2A is a syndrome of medullary thyroid carcinomas, pheochromocytomas and parathyroid hyperplasia. The simultaneous occurrence of medullary, and papillary, thyroid carcinomas is rare because they are derived from, apparently, different germ layers, the former from the neuroectoderm and the latter from the endoderm. We report a case of a papillary thyroid carcinoma, combined with a medullary thyroid carcinoma, in a patient with MEN type 2A. Molecular genetic studies for screening a RET proto-oncogene mutation revealed a point mutation in codon 631 on chromosome 10, which is reported as highly uncommon in MEN type 2A.