The creation of a new patient-derived xenograft (PDX) model of TFE3-fusion translocation renal cell carcinoma (tRCC) has enabled the identification of dysregulated PI3K–AKT–mTOR signalling in this disease. Dual PI3K–mTOR inhibition had antitumour activity in vitro and in vivo, providing a novel line of enquiry for drug development for this difficult-to-treat malignancy.
Samples from a lymph node metastasis of micropthalmis transcription factor family tRCC were cultured in mice and then harvested to establish a cell line and for histological and molecular characterization. The resulting RP-R07 cells and PDXs retained the histological features of the original metastasis and had the same strong TFE3 nuclear immunoreactivity. RNA sequencing identified a fusion transcript spanning SFPQ and TFE3.
Analysis of the molecular pathways targeted by the SFPQ–TFE3 fusion gene showed that the PI3K–AKT–mTOR axis was consistently influenced, and many genes related to this pathway were identified as targets of the SFPQ–TFE3 fusion. Disproportionate upregulation of the PI3K–AKT–mTOR pathway was observed in three tRCC cell lines.
In vitro, testing of three vertical inhibition schemas to target the PI3K–AKT–mTOR axis showed that simultaneous inhibition of PI3K and mTOR with a dual inhibitor had more antiproliferative activity than PI3K–AKT or mTOR inhibition alone in tRCC. Silencing of TFE3 using small interfering RNA inhibited RP-R07 cell proliferation.
In vivo, treatment with a dual PI3K and mTOR inhibitor resulted in significantly lower RP-R07 PDX tumour weight than control treatment.
Overall, these data suggest that targeting the PI3K–AKT–mTOR axis has therapeutic potential in TFE3-fusion tRCC.
Damayanti, N. P. et al. Therapeutic targeting of TFE3/IRS-1/PI3K/mTOR axis in translocation renal cell carcinoma. Clin. Cancer Res. https://doi.org/10.1158/1078-0432.CCR-18-0269 (2018)
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Stone, L. Targeting TFE3-fusion translocation RCC. Nat Rev Urol 15, 658 (2018). https://doi.org/10.1038/s41585-018-0080-3