Tyrosine Kinase Inhibitors Diminish Renal Neoplasms in a Tuberous Sclerosis Model Via Induction of Apoptosis.

Abstract

Tuberous sclerosis complex (TSC) tumors are presently incurable despite a cytostatic response to mTOR pathway inhibition because recurrence of disease occurs after treatment is discontinued. Here, we explored the hypothesis that inhibiting tyrosine kinase activity in mesenchymal lineage-specific platelet-derived growth factor receptor β (PDGFRβ) signaling in TSC tumors is cytocidal and attenuates tumorigenesis at significantly higher levels than treatment with an mTOR inhibitor. Rapamycin-induced versus tyrosine kinase inhibitor (TKI)-induced renal angiomyolipoma (AML) and pulmonary lymphangioleiomyomatosis (LAM) tumor cells were comparatively analyzed using cell survival assays, 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; 400 mg/kg/d; oral gavage) compared with Tsc2+/- mice treated with 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 with 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.

• Authors: Uchenna Unachukwu, Jarrod Sonett, Denzel Woode, Takayuki Shiomi, Kiran Chada, Jeanine M D'Armiento
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 22 Issue 7 Pg. 844-858 (07 05 2023) ISSN: 1538-8514 [Electronic] United States
• PMID: 37127876 (Publication Type: Journal Article, Research Support, U.S. Gov't, Non-P.H.S., Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2023 The Authors; Published by the American Association for Cancer Research.

Chemical References

• Tumor Suppressor Proteins
• Tyrosine Protein Kinase Inhibitors
• Imatinib Mesylate
• TOR Serine-Threonine Kinases

Topics

• Mice
• Animals
• Tuberous Sclerosis (drug therapy, genetics, metabolism)
• Angiomyolipoma (drug therapy, genetics, metabolism)
• Tumor Suppressor Proteins (genetics)
• Tyrosine Protein Kinase Inhibitors
• Kidney Neoplasms (pathology)
• Imatinib Mesylate (pharmacology)
• Mice, Inbred C57BL
• TOR Serine-Threonine Kinases (metabolism)
• Apoptosis
• Leukemia, Myeloid, Acute