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EXPERIMENTAL CANCERRESEARCH/ THERAPY

Role of the TOR pathway13.4.2007

christoph.moroni@unibas.ch

Introduction

C G Proud Oncogene 25: 6346;

Upstream of the mammalian target of rapamycin: do all

roads pass through mTOR?

M N Corradetti and K-L Guan Oncogene 25: 6347-6360;

Insulin and amino-acid regulation of mTOR signaling and

kinase activity through the Rheb GTPase

J Avruch, K Hara, Y Lin, M Liu, X Long, S Ortiz-Vega and K Yonezawa Oncogene 25: 6361-6372;

Stress and mTORture signaling

J H Reiling and D M Sabatini Oncogene 25: 6373-6383;

Ribosome biogenesis and cell growth: mTOR coordinates

transcription by all three classes of nuclear RNA

polymerases C Mayer and I Grummt Oncogene 25: 6384-6391;

Cell growth control: little eukaryotes make big

contributions

C De Virgilio and R Loewith Oncogene 25: 6392-6415;

mTOR, translation initiation and cancer Y Mamane, E Petroulakis, O LeBacquer and N Sonenberg Oncogene 25: 6416-6422;

When translation meets transformation: the mTOR story J Averous and C G Proud Oncogene 25: 6423-6435;

mTOR and cancer therapy

J B Easton and P J Houghton Oncogene 25: 6436-6446;

OncogeneVol. 25, 2005

Issue on TORDiscovery of Rapamycin

• Microorganism found on the Easter Islands• chemistry: macrolide antibiotic• inhibits T cell proliferation• clinically used as immunosuppressant• acts via FKBP12, an isomerase• targets TOR• in evaluation as antineoplastic agent

Betz 07Nature441,424-430(2006)

Nature 441, 424-430 (2006)

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M N Corradetti and K-L GuanOncogene (2006) 25, 6347 Stephan Wullschleger et al. Cell 2006; 124: 471-484

Nature 441, 424-430 (2006)

GAP

G-protein

S/T-kinase Translationinitiationfactor Ribosomal protein

S/T-kinase, rapa.sens.

wnt-GSK

ras-erk

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Nature Genetics 37, 19 (2005)Ken Inoki et al

Nature Genetics 37, 19 (2005)Ken Inoki et al

J Averous and C G ProudOncogene (2006) 25

S6K1SUMMARY

• TOR is a S-T kinase integratinggrowth,energy and metabolic signals

• TOR is controled via TSC2-Rheb

• TSC2 is a p-target of several kinases

• TSC1, -2, PTEN, LKB, NF1 are tumorsuppressors influencing TOR

• TOR forms TRC1 and -2 complexes

SUMMARY II

• TORC1 is rapa. sensitive and controlstranslation via S6K1 and 4E-BP

• S6K1 inhibits insulin-R activation of PKB(neg. feedback)

• TORC2 affects cytoskeleton and activatesPKB (pos. feedback), insensitive torapamycin

TOR and Cancer• No TOR mutations in cancer, but

elevated activity in over 50% of cancers• Upstream regulators of TOR are tumor

suppressors (TSC1, TSC2, PTEN,NF1,LKB)

• Donwstream target of TOR (eIF-4E isoncogenic in exp. Models

• Activation of TOR via siRNA to TSC2transforms hemopoietic cells

• Rapamycin has promising effects insome tumors (phase II and III studies)