Identification and characterization of RET fusions in advanced colorectal cancer
Anne-France Le Rolle1,2, Samuel J Klempner1,2, Christopher R Garrett3
1Division of Hematology/Oncology, Department of Medicine, University of California Irvine, Irvine, CA, USA.
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.
Insights
Researchers identified novel RET fusions in metastatic colorectal cancer (CRC) patients. These RET fusions are potential targets for new therapies, showing promise for improved treatment outcomes in advanced CRC.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Metastatic colorectal cancer (CRC) lacks sufficient molecularly targeted therapies.
- Comprehensive genomic profiling (CGP) can reveal actionable genomic alterations in cancer.
Purpose of the Study:
- To prospectively identify and characterize RET fusion kinases in metastatic CRC patients.
- To assess the potential of RET fusions as novel oncogenic drivers and therapeutic targets in CRC.
Main Methods:
- Prospective comprehensive genomic profiling of metastatic colorectal cancer patients.
- Identification and characterization of RET fusion kinases, including novel variants.
- In vitro assessment of RET kinase inhibitor efficacy on cancer cell lines.
Main Results:
- Six RET fusion kinases were identified in metastatic CRC, including two novel fusions (CCDC6-RET, NCOA4-RET).
- RET fusions occurred in 0.2% of patients, independent of common driver mutations (KRAS, NRAS, BRAF, PIK3CA) or other fusion tyrosine kinases.
- RET kinase inhibitors demonstrated significant cytotoxicity against RET fusion-positive CRC cells but not against RET fusion-negative cells.
Conclusions:
- RET fusion kinases represent a novel class of oncogenic drivers in metastatic colorectal cancer.
- The identification of RET fusions suggests a subset of CRC patients may benefit from RET kinase inhibition therapy.
- This study highlights the therapeutic significance of prospective CGP in identifying novel targets for advanced CRC.
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