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GCC2-ALK as a targetable fusion in lung adenocarcinoma and its enduring clinical responses to ALK inhibitors.
Jiang, Junhong; Wu, Xue; Tong, Xiaoling; Wei, Wangzhi; Chen, Anan; Wang, Xiaonan; Shao, Yang W; Huang, Jianan.
Afiliación
  • Jiang J; Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China.
  • Wu X; Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Ontario, M5G 1L7, Canada.
  • Tong X; Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Ontario, M5G 1L7, Canada.
  • Wei W; Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Ontario, M5G 1L7, Canada.
  • Chen A; Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Ontario, M5G 1L7, Canada.
  • Wang X; Nanjing Geneseeq Technology Inc., Nanjing, Jiangsu, 210032, China.
  • Shao YW; Translational Medicine Research Institute, Geneseeq Technology Inc., Toronto, Ontario, M5G 1L7, Canada; School of Public Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. Electronic address: yang.shao@geneseeq.com.
  • Huang J; Department of Respiratory Medicine, The First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, 215006, China. Electronic address: jahuang@suda.edu.cn.
Lung Cancer ; 115: 5-11, 2018 01.
Article en En | MEDLINE | ID: mdl-29290262
ABSTRACT

OBJECTIVES:

ALK, RET and ROS1 fusions have been identified as treatable targets in 5%-15% of non-small-cell lung cancers, and thanks to the advanced sequencing technologies, their new partner genes have been steadily detected. Here we identified a rare fusion of ALK (GCC2-ALK) in a patient with advanced lung adenocarcinoma and monitored the treatment efficacy of ALK inhibitors on this patient. We further performed in vitro functional studies of this fusion protein for evaluating its oncogenic potential. MATERIALS AND

METHODS:

The GCC2-ALK fusion gene was identified by targeted next generation sequencing (NGS) from the tumor DNA samples, and its fusion product was confirmed by Sanger sequencing the cDNA product. The functional study of GCC2-ALK was performed in Ba/F3 cells with cell proliferation and viability assays. The activation of downstream signaling pathways of ALK and their responses to crizotinib inhibition were studied in HEK-293 and 293T cells with ectopic expression of GCC2-ALK. In parallel, disease progression in the patient was monitored by computed tomography scanning and targeted NGS of either liquid or tissue biopsy samples throughout and after crizotinib treatment.

RESULTS:

Similarly to EML4-ALK, the GCC2-ALK fusion protein promotes IL-3-independent growth of Ba/F3 cells. Ectopic expression of GCC2-ALK leads to hyper-activation of ALK downstream signaling that can be inhibited by crizotinib. Crizotinib treatment of the patient resulted in 18 months of progression free survival without any trace of GCC2-ALK fusion in the liquid biopsies. Re-biopsy of a lung lesion at progression identified the re-occurrence of GCC2-ALK. The patient was then administrated with a second-generation ALK inhibitor, ceritinib, and received partial response until the last follow-up.

CONCLUSION:

We identified and functionally validated GCC2-ALK as a constitutively activated fusion in NSCLC. The patient was benefited from crizotinib treatment initially and then ceritinib after progression, suggesting GCC2-ALK as a novel therapeutic target for ALK inhibitors.
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Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Adenocarcinoma / Proteínas de Fusión Oncogénica / Quinasa de Linfoma Anaplásico / Proteínas de la Matriz de Golgi / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Adult / Female / Humans Idioma: En Revista: Lung Cancer Asunto de la revista: NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: China

Texto completo: 1 Banco de datos: MEDLINE Asunto principal: Adenocarcinoma / Proteínas de Fusión Oncogénica / Quinasa de Linfoma Anaplásico / Proteínas de la Matriz de Golgi / Neoplasias Pulmonares Tipo de estudio: Prognostic_studies Límite: Adult / Female / Humans Idioma: En Revista: Lung Cancer Asunto de la revista: NEOPLASIAS Año: 2018 Tipo del documento: Article País de afiliación: China