Gene interactions and pathways from curated databases and text-mining
Molecular cancer 2009, PMID: 19527517

Equivalent benefit of mTORC1 blockade and combined PI3K-mTOR blockade in a mouse model of tuberous sclerosis.

Pollizzi, Kristen; Malinowska-Kolodziej, Izabela; Stumm, Michael; Lane, Heidi; Kwiatkowski, David

BACKGROUND

Tuberous sclerosis (TSC) is a hamartoma syndrome in which renal and lung tumors cause the greatest morbidity. Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT. Recent studies indicate that inhibition of mTORC1 with RAD001 (everolimus) leads to rebound activation of AKT, which could protect tumors from drug-induced cell death. Here we examine the potential benefit of inhibition of both mTOR and AKT signaling in a mouse model of TSC, using a dual pan class I PI3K/mTOR catalytic small molecule inhibitor NVP-BEZ235.

RESULTS

Using ENU to enhance Tsc2+- kidney tumor development, both RAD001 (10 mg/kg PO 5 d/week) and NVP-BEZ235 (45 mg/kg PO QD) had equivalent effects in suppressing tumor development during a 4 week treatment period, with a 99% reduction in tumor cell mass. Marked reduction in activation of mTORC1, induction of cell cycle arrest, and absence of apoptotic cell death was seen in mice treated with either drug. However, when either was discontinued, there was prompt recovery of tumor growth, with extensive proliferation.

CONCLUSIONS

Both mTORC1 blockade alone and combined PI3K-mTOR blockade lead to suppression of tumor development but not tumor elimination in this TSC model.

Diseases/Pathways annotated by Medline MESH: Disease Models, Animal, Kidney Neoplasms, Neoplasm Recurrence, Local, Tuberous Sclerosis
Document information provided by NCBI PubMed

Text Mining Data

mTORC1 ⊣ TSC1: " Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT "

mTORC1 ⊣ TSC2: " Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT "

AKT → TSC1: " Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT "

AKT → TSC2: " Loss of either TSC1 or TSC2 in TSC hamartomas leads to activation of mTORC1 and suppression of AKT "

AKT ⊣ mTORC1: " Recent studies indicate that inhibition of mTORC1 with RAD001 ( everolimus ) leads to rebound activation of AKT , which could protect tumors from drug induced cell death "

Manually curated Databases

No curated data.