PI3K/Akt/mTOR
I SEGNI CARDINALI DEL CANCRO E
I MOLTEPLICI RUOLI DI AKT
Autosufficienza rispetto ai segnali di crescita e
insensibilità ai segnali antiproliferativi :
La sovraespressione di Akt può mediare un
aumento della risposta cellulare ai livelli di fattori
di crescita presenti nell’ambiente extracellulare
Akt promuove la localizzazione nucleare di
Mdm2, favorendone l’azione di inibizione su p53
Akt promuove la localizzazione citoplasmatica di
CKI quali p21 e p27, inibendone la funzione
Akt stabilizza i livelli di cicline D1 e D3
I SEGNI CARDINALI DEL CANCRO E
I MOLTEPLICI RUOLI DI AKT
Inibizione del processo apoptotico:
Akt inattiva i fattori proapoptotici Bad e
(pro)caspasi-9
Akt attiva IKK promuovendo la trascrizione di
geni antiapoptotici da parte di NFκB
Akt inattiva i fattori di trascrizione Forkhead,
inibendo la sintesi di FasL
I SEGNI CARDINALI DEL CANCRO E
I MOLTEPLICI RUOLI DI AKT
Potenziale replicativo illimitato:
Akt aumenta l’attività telomerasica fosforilando
hTERT
I SEGNI CARDINALI DEL CANCRO E
I MOLTEPLICI RUOLI DI AKT
Angiogenesi:
Akt attiva la nitrossido sintetasi endoteliale
(eNOS), promuovendo il processo angiogenico
I SEGNI CARDINALI DEL CANCRO E
I MOLTEPLICI RUOLI DI AKT
Invasività e metastasi :
Akt contribuisce al potenziale invasivo
stimolando la produzione di metalloproteinasi
della matrice (MMPs)
mTOR Inhibitors: Exploiting New
Targets in Cancer
Endothelial Cell
Cancer Cell
Growth
Factors
Nutrients
VEGFR
PDGFR-b
PI3K
mTOR
Akt
Protein Synthesis
Cell Growth
& Proliferation
mTOR
Tumor
Bioenergetics
Angiogenic
Factors
Vascular Cell
Growth
Vascular Pericyte
13
mTOR Coordinates
Growth and Nutrient Signaling
Blood Vessel
Nutrient Availability
Growth Factors
Increased
Nutrient Uptake
Nutrients
mTOR
Secretion of Angiogenic
Growth Factors
M
G1
G2
Cell Cycle Activation
S
14
mTOR is a Central Regulator
of Growth and Metabolism
Growth Factors
Nutrients
 mTOR is an intracellular
serine/threonine kinase
 mTOR is a central regulator that
senses changes in
– Availability of growth
factors1,2
mTOR
– Availability of nutrients1,2
– Availability of fuel/energy3
Protein Synthesis
 mTOR regulation can affect
Cell Growth
& Proliferation
Bioenergetics
Angiogenesis
Normal Cell
– Angiogenesis4
– Cell growth3
– Nutrient uptake, utilization5
– Metabolism3
15
mTOR Integrates Growth Factor Signaling
↓Glucose
↑Glucose
↓ATP
PI3K
AMPK
TSC1
↑ATP
TSC2
Akt
Growth
Signaling
Amino
Acids
 mTOR activation turns on the
synthesis of proteins involved in
cell growth2
mTOR
Protein Synthesis
Cell Growth
& Proliferation
 mTOR pathway, PI3K-AKTmTOR, is a downstream
component of several growth
factor signaling pathways1
 mTOR is a critical integrator of
signaling that coordinates cell
growth control3
Bioenergetics
Angiogenesis
16
mTOR Integrates Nutrient Signaling
↓Glucose
↑Glucose
↓ATP
PI3K
AMPK
TSC1
↑ATP
TSC2
Growth
Signaling
Akt
Amino
Acids
mTOR
Protein Synthesis
Cell Growth
& Proliferation
 mTOR senses availability of
amino acids, metabolic fuel, and
energy1
 Nutrients and energy stores are
essential for protein synthesis,
cell growth, proliferation, and
survival1,2,3
 mTOR activation supports
growth and survival by
increasing cell access to
nutrients and metabolic fuels4
Bioenergetics
Angiogenesis
17
mTOR Pathway Regulates Bioenergetics
 Bioenergetics refers to nutrient utilization and metabolism
 mTOR senses nutrient and energy availability in a cell
 mTOR pathway activation controls bioenergetics by
increasing nutrient transporter expression and production of
angiogenic growth factors
 mTOR pathway activation controls bioenergetics by
enabling the influx of glucose, amino acids, and other
important molecules that are metabolic fuels used to
generate ATP
 Targeting the mTOR pathway can impact the bioenergetics
of the cell
18
mTOR Pathway is Deregulated
by Mutations in Cancer
IGF
EGF
Growth
Signaling
VEGF
Nutrients
Ras
 Normal cell growth, proliferation,
and metabolism are maintained by
a number of mTOR regulators1,2
PTEN
Abl
ER
PI3K
 Regulators of mTOR activity
Ras
TSC1
mTOR activating
Akt
TSC2
mTOR deactivating
 Deregulation of mTOR can result
in loss of growth control and
metabolism1,3
mTOR
Protein Synthesis
Cell Growth
& Proliferation
Bioenergetics
 Mutations in the mTOR pathway
have been linked to specific
cancers4
Angiogenesis
Cancer Cell
19
mTOR Pathway is Deregulated in Many Cancers
Brain
Thyroid
Oral
SCC
Breast
Lung
Blood
Kidney
Ovary
Pancreas
Colon
Uterus
Prostate
Skin
Sarcoma
20
mTOR Pathway is Deregulated in Select Cancers
p-Akt, 23%–50%18
PTEN, 24%22
Ras, 30%12
EGFR, 32%–60%1
Breast
Lung
NET
TSC1/TSC240
p-Akt, 42%16
PI3K, 18%–26%27,28
PTEN, 15%–41%25
HER2, 30%–36%26,27
TSC1/TSC231,32
IGF-1/IGF-1R33
VHL34
p-Akt, 38%38
PTEN, 31%39
TGFa/TGFb1,
60%–100%35
VHL, 30%–50%36,37
IGF-1/IGF-IR,
39%-69%9
Kidney
% Incidence of mutation in select cancer
Colon
p-Akt, 46%15
PI3K, 20%–32%13,41
PTEN, 35%41
Ras, 50%12
EGFR, 70%42
21
mTOR Activation Supports Cancer Cell Growth
Nutrients
Growth
Signaling

Cancer cells have deregulated
growth

Key proteins are regulated by
mTOR activation:
mTOR
S6K1
4E-BP1
elF-4E
S6
Protein Synthesis
Cyclin D
HIF-1a
Cell
Growth
Angiogenesis
Glut 1
LAT1
Nutrient
Uptake &
Metabolism

–
Cell cycle regulators1
–
Proangiogenic factors2
–
Amino acid and glucose
transporters3,4
mTOR activation supports
cancer cell growth by
stimulating the synthesis of
proteins important for cell
growth, angiogenesis, nutrient
uptake, and metabolism
22
mTOR Activates Cell Cycle Progression
mTOR
M
G2
Protein Synthesis
G1
S
Restriction
point
Cyclin D1
Israels and Israels. Oncologist. 2000;5:510-513, with permission.
23
mTOR Pathway Activation Promotes Angiogenesis
Secretion of Angiogenic Growth Factors
mTOR
VHL
 Angiogenesis enables cancer
cells access to growth factors,
nutrient and energy resources1
Protein Synthesis
 mTOR activation elevates protein
synthesis of HIF-1a and HIF-2a2
HIF1/2
 HIF turns on several hypoxic
stress genes including VEGF and
PDGF-b3
Hypoxic Stress Genes
Angiogenic Factors
 Cancer cells secrete the
proangiogenic factors that
promote the formation of new
vessels1,4,5
Secretion
24
mTOR Pathway Activation Promotes Angiogenesis
Growth Control of Vascular Cells
VEGF
PDGF
Endothelial Cell
VEGFR
Cancer Cell
PI3
PDGFR-b
K
mTOR
Akt
Protein Synthesis
mTOR
VHL
HIF1/2
Hypoxic Stress Genes
Angiogenic
Growth Factors
Tumor
Tumor
Vascular Cell Growth
Angiogenesis
Vascular Pericyte
25
mTOR Activation Increases Nutrient Uptake
Amino
Acids
Glucose
Nutrients
GLUT 1
LAT
 Cancer cells have increased
nutrient and metabolic needs
 Adequate amino acids, glucose,
and ATP are required to sustain
cancer cell growth
mTOR
 Nutrients and metabolic fuel are
taken up via nutrient transporters
 mTOR activation can increase the
expression of nutrient transporters
Protein Synthesis
Amino Acid and
Glucose Transporters
 Cancer cell access to nutrients
and metabolic fuel support
unregulated cell growth
26
mTOR Coordinates Cancer Cell Growth
Blood Vessel
Nutrient Availability
Glucose
Transporter
Production
Increasedof
Transporters
Nutrient
Uptake
mTOR
Secretion of Angiogenic
Growth Factors
Mutations in
Cancer
Amino Acid
Transporter
M
G1
G2
Cancer Cell Growth
S
Cancer Cell
27
mTOR Inhibition May Disrupt
Cancer Cell Growth by Various Ways
Blood Vessel
Nutrient Availability
DECREASED
Secretion of Angiogenic
Growth Factors
Glucose
Transporter
mTOR
DECREASED
Amino Acid
Transporter
M
G1
G2
Cancer Cell Growth
S
Cancer Cell
28
The role of programmed cell death in tumor development
Deirdre A. Nelson et al. Genes Dev. 2004; 18: 1223-1226
hypoxic
autophagy
Differenze nella risposta di cellule normali e tumorali allo stress metabolico
In che modo è possibile manipolare il metabolismo delle cellule tumorali in
modo da indurre la morte cellulare attraverso una catastrofe metabolica?
Figure 16.43a The Biology of Cancer (© Garland Science 2007)
Figure 16.43b The Biology of Cancer (© Garland Science 2007)
mTOR Inhibition May Enhance the
Antitumor Effects of Other Therapies
Radiation
Chemotherapy
mTOR
Inhibition
Growth Factor
Signaling
Inhibitors
Antiestrogens
Antiangiogenics
47
Combination Therapy Rationale
mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies
Agent
Rationale
EGFR inhibitors
Defects in the mTOR signaling pathway may counter the effects of
EGFR inhibitors on cell growth and proliferation. Combined treatment
has been beneficial in preclinical studies1
Cytotoxic
chemotherapy
Cytotoxic drugs such as the platinum derivatives, taxanes,
anthracyclines, and gemcitabine have shown improved antitumor
effects in preclinical models when used in combination with mTOR
inhibitors2-4
Antiangiogenic
agents
mTOR inhibition affects angiogenesis through mechanisms that
enhance and complement those of anti-VEGF/anti-VEGFR signaling
inhibitors5
Antiestrogens
Defects in the mTOR signaling pathway may render estrogendependent tumor cells resistant to antiestrogens and aromatase
inhibitors. Combinations effective preclinically6-8
Radiation
In preclinical studies, mTOR inhibition enhances cell killing induced
by radiation, possibly by interfering with repair of damage to DNA9
48