Tyrosine Kinase Inhibitors Diminish Renal Neoplasms in a Tuberous Sclerosis Model via induction of Apoptosis.

Tuberous Sclerosis Complex (TSC) tumors are presently incurable despite a cytostatic response to mTOR pathway inhibition since recurrence of disease occurs after discontinuation of treatment. Here, we explored the hypothesis that inhibiting tyrosine kinase activity in mesenchymal lineage specific platelet derived growth factor receptor beta (PDGFRβ) signaling in TSC tumors is cytocidal and attenuates tumorigenesis at significantly higher levels than treatment with an mTOR inhibitor. Rapamycin- versus tyrosine kinase inhibitor (TKI)-induced renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) tumor cells were comparatively analyzed using cell survival assays, and RNA sequencing and bioinformatics to distinguish tumoricidal mechanisms adopted by each drug type. The efficacy of imatinib therapy was validated against spontaneously developing renal cystadenomas in Tuberous Sclerosis Tsc2+/- mouse models (C57BL/6J mice; N=6; 400mg/kg/day; oral gavage) compared to Tsc2+/- mice treated with phosphate buffered saline (PBS) (C57BL/6J mice; N=6). Our study revealed that TKIs imatinib and nilotinib were cytocidal to both pulmonary LAM and renal AML cell cultures through the downregulation of the glycoprotein GPVI pathway and resultant disruption in mitochondrial permeability, increased cytosolic cytochrome C, and caspase 3 activation. Importantly, renal tumor growth was significantly attenuated in imatinib-treated Tsc2+/- mice compared to PBS treatment. The preclinical studies reported here provide evidence documenting the effectiveness of TKIs in limiting LAM and AML cell growth and viability with important clinical potential. Furthermore, these drugs elicit their effects by targeting a PDGF pathway-dependent apoptotic mechanism supporting the investigation of these drugs as a novel class of TSC therapeutics.