Abstract
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.
Highlights
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States
We identified two novel RET fusion www.impactjournals.com/oncotarget kinases involving 5’ fusion partners Coiled Coil Domain Containing 6 (CCDC6) and Nuclear Receptor Coactivator 4 (NCOA4) in two patients with metastatic CRC
Our data suggest that CRC patients who harbor RET fusion kinase without a concurrent driver mutation may respond to regorafenib, a potent RET kinase inhibitor with an IC50 of ~ 1.5n M [12]
Summary
Colorectal cancer (CRC) is the second most common cause of cancer-related death in the United States. Recent molecular characterization of CRC has not yet been translated into effective therapeutic strategies [2], comprehensive genomic profiling has emerged as a promising approach that enables the identification of genomic biomarkers that may inform the use of targeted therapy in clinical trials. This therapeutic genomic paradigm is best demonstrated in tumors that are driven by activated protein tyrosine kinases due to oncogenic mutations or rearranged chromosomal fusion [3]. Evidence of therapeutic response in CRC patient with a CCDC6-RET fusion treated with the RET kinase inhibitor regorafenib highlights the therapeutic importance of genomic profiling in colorectal cancer
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