Abstract
Tuberous sclerosis (TSC) is an inherited tumour syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR. Tumour responses in TSC patients to rapamycin, an allosteric inhibitor of mTOR, or its analogs are partial and reversible probably due to feedback activation of Akt. In this study, we examined the efficacy of GSK2126458, an ATP-competitive dual inhibitor of PI3K/mTOR, in comparison to rapamycin for treatment of renal tumours in genetically engineered Tsc2+/- mice. We found that both GSK2126458 and rapamycin caused significant reduction in number and size of solid renal tumours. GSK2126458 also significantly reduced the number and size of all lesions (cystic, papillary and solid) although to a lesser extent compared to rapamycin. GSK2126458 inhibited both PI3K and mTOR while rapamycin exerted stronger inhibitory effect on mTORC1 in renal tumours. Furthermore, GSK2126458 and rapamycin suppressed proliferation of tumour cells. Importantly, GSK2126458 increased apoptosis of solid tumours but rapamycin did not. Further investigations are therefore needed to test whether rapamycin in combination with GSK2126458 could promote apoptosis and thus improve therapy of TSC-associated renal tumours.
Highlights
Tuberous sclerosis (TSC) is an inherited tumour syndrome caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR
We examined the efficacy of GSK2126458, an ATP-competitive dual inhibitor of PI3K/mTOR, in comparison to rapamycin for treatment of renal tumours in genetically engineered Tsc2+/- mice
Tuberous sclerosis (TSC) is an inherited disease caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumours in multiple organs
Summary
Tuberous sclerosis (TSC) is an inherited disease caused by mutations in TSC1 or TSC2 that lead to aberrant activation of mTOR and development of tumours in multiple organs. TSC patients frequently develop renal manifestations, usually multiple and bilateral angiomyolipomas (AML) that are the leading cause of adult deaths from the disease. Treatment with the mTOR inhibitor rapamycin (sirolimus) or its derivative everolimus significantly reduces the size of renal AML in TSC patients [2,3,4]. Everolimus has demonstrated clinical efficacy in TSC-associated renal carcinoma [5]. Responses of AML and other TSC-associated tumours to these mTOR inhibitors are partial and tumours that initially respond to treatment usually regrow after drug withdrawal. Partial resistance to rapamycin or its derivatives is suggested to be associated with loss of negative feedback regulation that leads to increased phosphorylation and activation of AKT [6]
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