Abstract
We investigated the patients with solid cancers harboring Fms-like tyrosine kinase 3 (FLT3) amplification using targeted sequencing of tumor tissue specimen and FISH assay. Simultaneously, FLT3-amplified patient-derived cells (PDCs) were generated to evaluate the sensitivity to FLT3 inhibition. A patient with metastatic colon cancer who was previously treated with more than 3rd line cytotoxic chemotherapy was found to have FLT3 amplification and then received regorafenib showing partial response. In two PDC cell lines with FLT3 amplification, FLT3 mRNA expression was increased, however, the growth of tumor cells was not significantly inhibited by either regorafenib or sorafenib which is known to block the activity FLT3. Additional drug combinations with mTOR inhibitor did not affect the cell proliferation of PDC. FLT3 amplification in solid cancers is infrequently observed using targeted genomic profile, as yet, FLT3 amplification does not seem to be an actionable target or a proper biomarker for FLT3 inhibitor sensitivity.
Highlights
Fms-like tyrosine kinase-3 (FLT3) is a gene that encodes for a tyrosine kinase that activates pathway in proliferation and differentiation of hematopoietic stem cells
We investigated the patients with solid cancers harboring Fms-like tyrosine kinase 3 (FLT3) amplification using targeted sequencing of tumor tissue specimen and fluorescence in situ hybridization (FISH) assay
In the TCGA data set, the incidence of FLT3 amplification was highest in colorectal cancer (34.6%), breast cancer (10.5%), and gastric cancer
Summary
Fms-like tyrosine kinase-3 (FLT3) is a gene that encodes for a tyrosine kinase that activates pathway in proliferation and differentiation of hematopoietic stem cells. In cancer cells with activating mutations in FLT3, FLT3 inhibitors or tyrosine kinase inhibitors have been shown to be effective [5, 6] and a number of small-molecule tyrosine inhibitors of FLT3 have been developed and trials are ongoing. The role of FLT3 gene aberration in solid tumors has not yet been established. A comprehensive analysis of FLT3 aberrations showed that the majority are somatic mutations, followed by gene amplification [7]. It remains unknown that FLT3 amplification might be potentially actionable molecular alterations in certain tumor types, in the current study, we investigated patients with solid cancers majority of gastrointestinal malignancies harboring of FLT3 amplification and the clinical efficacy of FLT3 inhibition in this subpopulation. We further generated patient derived cells (PDC) from some of these patients’
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