Identification and characterization of RET fusions in advanced colorectal cancer
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Anne-France Le Rolle1,2,*, Samuel J. Klempner1,2,*, Christopher R. Garrett3, Tara Seery1,2, Eric M. Sanford4, Sohail Balasubramanian4, Jeffrey S. Ross4,5, Philip J. Stephens4, Vincent A. Miller4, Siraj M. Ali4 and Vi K. Chiu1,2
1 Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Irvine, CA, USA
2 Chao Family Comprehensive Cancer Center, University of California Irvine, Orange, CA, USA
3 The Division of Cancer Medicine, Department of Gastrointestinal Medical Oncology, MD Anderson Cancer Center, Houston, TX, USA
4 Foundation Medicine Inc., Cambridge, MA, USA
5 Albany Medical College, Albany, NY, USA
* These authors have contributed equally to this work
Vi K. Chiu, email:
Keywords: RET fusion kinase, RET kinase inhibitor, comprehensive genomic profiling, colorectal cancer
Received: April 02, 2015 Accepted: May 12, 2015 Published: May 30, 2015
There is an unmet clinical need for molecularly directed therapies available for metastatic colorectal cancer. Comprehensive genomic profiling has the potential to identify actionable genomic alterations in colorectal cancer. Through comprehensive genomic profiling we prospectively identified 6 RET fusion kinases, including two novel fusions of CCDC6-RET and NCOA4-RET, in metastatic colorectal cancer (CRC) patients. RET fusion kinases represent a novel class of oncogenic driver in CRC and occurred at a 0.2% frequency without concurrent driver mutations, including KRAS, NRAS, BRAF, PIK3CA or other fusion tyrosine kinases. Multiple RET kinase inhibitors were cytotoxic to RET fusion kinase positive cancer cells and not RET fusion kinase negative CRC cells. The presence of a RET fusion kinase may identify a subset of metastatic CRC patients with a high response rate to RET kinase inhibition. This is the first characterization of RET fusions in CRC patients and highlights the therapeutic significance of prospective comprehensive genomic profiling in advanced CRC.
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