RESUMEN
BACKGROUND: Mammary analogue secretory carcinoma (MASC) is a recently described pathologic entity. We report the case of a patient with an initial diagnosis of salivary acinic cell carcinoma later reclassified as MASC after next-generation sequencing revealed an ETV6-NTRK3 fusion. PATIENTS AND METHODS: This alteration was targeted with the pan-Trk inhibitor entrectinib (Ignyta), which possesses potent in vitro activity against cell lines containing various NTRK1/2/3 fusions. RESULTS: A dramatic and durable response was achieved with entrectinib in this patient, followed by acquired resistance that correlated with the appearance of a novel NTRK3 G623R mutation. Structural modeling predicts that this alteration sterically interferes with drug binding, correlating to decreased sensitivity to drug inhibition observed in cell-based assays. CONCLUSIONS: This first report of clinical activity with TrkC inhibition and the development of acquired resistance in an NTRK3-rearranged cancer emphasize the utility of comprehensive molecular profiling and targeted therapy for rare malignancies (NCT02097810).
Asunto(s)
Benzamidas/administración & dosificación , Carcinoma de Células Acinares/diagnóstico , Indazoles/administración & dosificación , Carcinoma Secretor Análogo al Mamario/diagnóstico , Proteínas de Fusión Oncogénica/genética , Neoplasias de las Glándulas Salivales/diagnóstico , Adulto , Benzamidas/efectos adversos , Biomarcadores de Tumor/genética , Carcinoma de Células Acinares/tratamiento farmacológico , Carcinoma de Células Acinares/genética , Carcinoma de Células Acinares/patología , Ensayos Clínicos como Asunto , Crizotinib , Diagnóstico Diferencial , Resistencia a Antineoplásicos/genética , Femenino , Humanos , Hibridación Fluorescente in Situ , Indazoles/efectos adversos , Carcinoma Secretor Análogo al Mamario/tratamiento farmacológico , Carcinoma Secretor Análogo al Mamario/genética , Carcinoma Secretor Análogo al Mamario/patología , Mutación , Pirazoles/administración & dosificación , Piridinas/administración & dosificación , Neoplasias de las Glándulas Salivales/tratamiento farmacológico , Neoplasias de las Glándulas Salivales/genética , Neoplasias de las Glándulas Salivales/patologíaRESUMEN
The molecular mechanisms that control the surface expression of NMDA receptors (NMDARs) and AMPA receptors (AMPARs) are unknown. To determine the role of the intracellular C-terminal tails of glutamate receptor subunits in the synaptic targeting of AMPARs and NMDARs, we fused the tails of the AMPAR subunits, GluR1 and GluR2, and the NMDAR subunit, NR1, to the human T lymphocyte membrane protein CD8 and expressed these constructs in HEK293 cells and cultured hippocampal neurons. The GluR1 and GluR2 fusion proteins exhibited robust surface expression in the plasma membrane of neurons at synapses as did CD8 alone. In contrast, the NR1 fusion protein was retained intracellularly in both HEK293 cells and neurons because of the presence of an ER retention signal in the C1 cassette. This ER retention signal was overridden either by the addition of a PDZ domain-binding motif or by mimicking phosphorylation at a site adjacent to the retention signal. These results provide further evidence that the intracellular trafficking of AMPAR and NMDAR subunits are regulated independently at least in part because of differences in the protein-protein interactions of their intracellular C-terminal tails.
