Cooperative benefit for the combination of rapamycin and imatinib in tuberous sclerosis complex neoplasia

Abstract

Tuberous sclerosis (TS) is a common autosomal-dominant disorder characterized by tumors of the skin, lung, brain, and kidneys. Monotherapy with rapamycin however resulted in partial regression of tumors, implying the involvement of additional pathways. We have previously implicated platelet-derived growth factor-BB in TS-related tumorigenesis, thus providing a rationale for a combination of mTOR/PDGF blockade using rapamycin and imatinib. Here, we test this combination using a well-established preclinical model of cutaneous tumorigenesis in TS, tsc2ang1 cells derived from a skin tumor from a mouse heterozygous for tsc2. Treatment of tsc2ang1 cells with a combination of rapamycin and imatinib led to an inhibition of proliferation compared with either vehicle treatment or treatment with rapamycin or imatinib monotherapy. Combination therapy also led to a decrease in Akt activation. Potent in vivo activity in animal experiments by combination therapy was noted, without toxicity to the animals. Our findings provide a rationale for the combined use of rapamycin and imatinib, both FDA approved drugs, for the treatment of TS.

Exosomes mediate the acquisition of the disease phenotypes by cells with normal genome in tuberous sclerosis complex

“…46 The effect of exosomes on neo-angiogenesis is abrogated by the tyrosine kinase inhibitors, imatinib and dasatinib. 46 Given that imatinib was also shown to have more profound effect on Tsc2-null cell proliferation and tumor growth when combined with rapamycin in a mouse model of cutaneous tumorigenesis, 47 it is likely that the inhibitory effect of imatinib on exosome production is responsible for this result, therefore provides a rationale for combined therapy in TSC.…”

Tuberous Sclerosis Complex Axis Controls Renal Extracellular Vesicle Production and Protein Content

“…Our previous clinical study research found that rapamycin compounds could reduce the angiomyolipomata volume in TSC patients [43,44]. Interestingly, preclinical work suggests that a combination therapy of imatinib and rapamycin has more antitumor effect compared to rapamycin alone in an in vivo model of cutaneous tumorigenesis [45]. This improved effect could relate to the fact that tyrosine kinase inhibitors such as imatinib and dasatinib possess an inhibitory effect on EV production [46].…”

The changing face of a rare disease: lymphangioleiomyomatosis

“…An inverse relationship between mTOR activation and PDGFRβ levels in TSC-derived cells has also been shown [146]. In a preclinical model, nearly complete tumour inhibition with a combination of rapamycin and imatinib targeting two distinct signalling pathways (mTORC1 and PDGFRβ, respectively) has been observed, suggesting a rationale for the clinical use of this combination therapy for TSC and LAM [147].…”