PI3K/Akt/mTOR
ROLES OF AKT IN DETERMINING THE HALLMARKS OF CANCER
Self-sufficiency in growth signals and insensitivity to anti-growth signals:
Akt overexpression can mediate an increase in cellular response to growth factors in the extra-cellular space
Akt promotes cytoplasmic localization of CKIs, such as p21 and p27, thereby inhibiting their function
Akt stabilizes cyclin D1 e D3 levels
Akt facilitates MDM2 nuclear localization and its inhibitory action on p53
Inhibition of apoptosis
Akt inactivates the proapoptic factors Bad and (pro)caspase-9
Akt activates IKK enhancing NFκB transcriptional activity on antiapoptotic genes
Akt inactivates Forkhead transcription factors, inhibiting FasL synthesis
ROLES OF AKT IN DETERMINING THE HALLMARKS OF CANCER
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)
14
mTOR Inhibitors: Exploiting New Targets in Cancer
Vascular Cell Growth
Akt
PI3K
VEGFR PDGFR-
mTOR
Cancer Cell
Vascular Pericyte
Endothelial Cell
Tumor
Angiogenic Factors
Protein Synthesis
Bioenergetics
NutrientsGrowth Factors
mTOR
Cell Growth & Proliferation
15
mTOR
MG1
G2
S
Cell Cycle Activation
mTOR Coordinates Growth and Nutrient Signaling
IncreasedNutrient Uptake
Secretion of Angiogenic Growth Factors
Blood Vessel
Growth Factors
Nutrients
Nutrient Availability
16
mTOR is a Central Regulator of Growth and Metabolism
mTOR is an intracellular serine/threonine kinase
mTOR is a central regulator that senses changes in
– Availability of growth factors1,2
– Availability of nutrients1,2
– Availability of fuel/energy3
mTOR regulation can affect
– Angiogenesis4
– Cell growth3
– Nutrient uptake, utilization5
– Metabolism3
Cell Growth & Proliferation
Protein Synthesis
mTOR
Angiogenesis
Nutrients Growth Factors
Normal Cell
Bioenergetics
17
mTOR Integrates Growth Factor Signaling
mTOR pathway, PI3K-AKT-mTOR, is a downstream component of several growth factor signaling pathways1
mTOR activation turns on the synthesis of proteins involved in cell growth2
mTOR is a critical integrator of signaling that coordinates cell growth control3
mTOR
Growth Signaling
PI3K
AktTSC2
↑Glucose
TSC1
AMPK
Amino Acids
↑ATP
↓Glucose
↓ATP
Cell Growth & Proliferation
Protein Synthesis
Angiogenesis
Bioenergetics
18
mTOR Integrates Nutrient Signaling
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
mTOR
Growth Signaling
PI3K
AktTSC2
↑Glucose
TSC1
AMPK
Amino Acids
↑ATP
↓Glucose
↓ATP
Cell Growth & Proliferation
Protein Synthesis
Angiogenesis
Bioenergetics
19
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
20
mTOR Pathway is Deregulated by Mutations in Cancer
Normal cell growth, proliferation, and metabolism are maintained by a number of mTOR regulators1,2
Regulators of mTOR activity
mTOR activating
mTOR deactivating
Deregulation of mTOR can result in loss of growth control and metabolism1,3
Mutations in the mTOR pathway have been linked to specific cancers4
PTEN
TSC2
TSC1
mTOR
Cell Growth & Proliferation
Angiogenesis
Protein Synthesis
Bioenergetics
Akt
PI3K ERAbl
Ras
Ras
EGF
IGF
Nutrients
VEGF
Growth Signaling
Cancer Cell
21
mTOR Pathway is Deregulated in Many Cancers
Brain
Oral SCC
Breast
Pancreas
ColonUterus
Prostate
Skin
Ovary
BloodLung
Thyroid
Sarcoma
Kidney
22
mTOR Pathway is Deregulated in Select Cancers
Breast
NET
Colon
Lung
Kidney
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, 46%15
PI3K, 20%–32%13,41
PTEN, 35%41
Ras, 50%12
EGFR, 70%42
p-Akt, 23%–50%18
PTEN, 24%22
Ras, 30%12
EGFR, 32%–60%1
TSC1/TSC240
p-Akt, 38%38
PTEN, 31%39
TGF/TGF1, 60%–100%35
VHL, 30%–50%36,37
IGF-1/IGF-IR, 39%-69%9
% Incidence of mutation in select cancer
23
mTOR Activation Supports Cancer Cell Growth
Cancer cells have deregulated growth
Key proteins are regulated by mTOR activation:
– 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
Nutrients
Angio-genesis
Nutrient Uptake &
Metabolism
Glut 1LAT1
Cell Growth
mTOR
Protein Synthesis
Growth Signaling
4E-BP1
S6
S6K1
elF-4E
HIF-1Cyclin D
24
mTOR
mTOR Activates Cell Cycle Progression
Israels and Israels. Oncologist. 2000;5:510-513, with permission.
Restrictionpoint
G2
M
S
G1
Cyclin D1
Protein Synthesis
25
mTOR Pathway Activation Promotes AngiogenesisSecretion of Angiogenic Growth Factors
Angiogenesis enables cancer cells access to growth factors, nutrient and energy resources1
mTOR activation elevates protein synthesis of HIF-1 and HIF-22
HIF turns on several hypoxic stress genes including VEGF and PDGF-3
Cancer cells secrete the proangiogenic factors that promote the formation of new vessels1,4,5
HIF-1/2
mTOR
Hypoxic Stress Genes
Protein Synthesis
Angiogenic Factors
Secretion
VHL
26
mTOR Pathway Activation Promotes Angiogenesis
Growth Control of Vascular Cells
Vascular Cell Growth
Akt
PI3
K
VEGFR PDGFR-
mTOR
VEGF PDGF
Tumor
Angiogenesis
HIF-1/2
VHL
mTOR
Protein Synthesis
Hypoxic Stress Genes
AngiogenicGrowth Factors
Tumor
Cancer Cell
Vascular Pericyte
Endothelial Cell
27
mTOR Activation Increases Nutrient Uptake
mTOR
Protein Synthesis
AminoAcids Glucose
GLUT 1
Amino Acid and Glucose Transporters
Nutrients
LAT Cancer cells have increased
nutrient and metabolic needs
Adequate amino acids, glucose, and ATP are required to sustain cancer cell growth
Nutrients and metabolic fuel are taken up via nutrient transporters
mTOR activation can increase the expression of nutrient transporters
Cancer cell access to nutrients and metabolic fuel support unregulated cell growth
28
Production of Transporters
mTOR
MG1
G2
S
Cancer Cell Growth
mTOR Coordinates Cancer Cell Growth
GlucoseTransporter
IncreasedNutrient Uptake
Nutrient Availability
Secretion of Angiogenic Growth Factors
Cancer Cell
Amino AcidTransporter
Mutations in Cancer
Blood Vessel
29
mTOR
MG1
G2
S
Cancer Cell Growth
mTOR Inhibition May Disrupt Cancer Cell Growth by Various Ways
GlucoseTransporter
Secretion of Angiogenic Growth Factors
Cancer Cell
Amino AcidTransporter
Blood Vessel
DECREASED
Nutrient Availability
DECREASED
Sabatini Nature Reviews Cancer advance online publication;published online 17 August 2006 | doi:10.1038/nrc1974
Figure 16.44b The Biology of Cancer (© Garland Science 2007)
Figure 16.44c The Biology of Cancer (© Garland Science 2007)
41
mTOR Inhibitors Suppress Nutrient Availability
Vascular Cell Growth
Akt
VEGFR PDGFR-
mTOR
VEGF PDGF
Tumor
Protein Synthesis
Nutrient Uptake
NutrientsGrowth Factors
mTOR
NutrientTransporters
AngiogenicFactors
Secretion VEGF, PDGF
Angiogenesis
PI3K
42
mTOR Inhibition is a Novel Approach for Blocking Angiogenesis
Vascular Cell Growth
Akt
VEGFR
mTOR
VEGFPDGF
PDGFR-
Angiogenesis
Tumor
HIF1/2VHL
mTOR
Protein Synthesis
Hypoxic Stress Genes
AngiogenicGrowth Factors
TKI
VEGF mAb
PI3K
43
Growth factor inhibitors target either the growth factor or the receptor on the cell surface
mTOR inhibitors target cancer cell growth downstream of growth factor receptors
Combining an mTOR inhibitor with a growth factor receptor inhibitor may be a more effective strategy for cancer treatment
mTOR inhibitors may be effective in patients that are refractory to growth factor inhibition
mTOR
Cell Growth & Proliferation
Angiogenesis
Protein Synthesis
Akt
Growth FactormAb
TKI
Bioenergetics
mTOR Inhibition May Enhance the Antitumor Effects of Targeted Therapies
PI3K
44
mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies
mTORInhibition
Antiestrogens
RadiationChemotherapy
Growth Factor Signaling Inhibitors
Antiangiogenics
45
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 estrogen-dependent 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
Combination Therapy RationalemTOR Inhibition May Enhance the Antitumor Effects of Other Therapies
46
SummaryRationale for Targeting mTOR
Targeting deregulated pathways has been a successful clinical strategy
mTOR is a central regulator of cancer cell growth and metabolism Deregulation of components of the mTOR pathway occurs in many
types of hematologic and solid tumors
Targeting the mTOR pathway can impact the bioenergetics of the cell, a new approach in the treatment of cancer
mTOR is a unique target in cancer that may provide therapeutic benefit to patients with disease refractory to currently approved therapies
Therapeutic strategies combining mTOR inhibitors with other targeted therapies or cytotoxic agents may provide enhanced anticancer activity