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2017 ; 8
(35
): 58504-58512
Nephropedia Template TP
gab.com Text
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English Wikipedia
The dual PI3K/mTOR inhibitor GSK2126458 is effective for treating solid renal
tumours in Tsc2(+/-) mice through suppression of cell proliferation and induction
of apoptosis
#MMPMID28938574
Narov K
; Yang J
; Samsel P
; Jones A
; Sampson JR
; Shen MH
Oncotarget
2017[Aug]; 8
(35
): 58504-58512
PMID28938574
show ga
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.