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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 extracellular 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 ROLES OF AKT IN DETERMINING THE HALLMARKS OF CANCER 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 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 14 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 15 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 16 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 17 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 18 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 19 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 20 mTOR Pathway is Deregulated in Many Cancers Brain Thyroid Oral SCC Breast Lung Blood Kidney Ovary Pancreas Colon Uterus Prostate Skin Sarcoma 21 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 22 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 23 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. 24 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 25 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 26 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 27 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 28 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 29 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) mTOR Inhibitors Suppress Nutrient Availability VEGF Growth Factors Nutrients PDGF VEGFR PDGFR-b PI3K mTOR Akt mTOR Protein Synthesis Angiogenic Nutrient Factors Transporters Secretion VEGF, PDGF Nutrient Uptake Tumor Vascular Cell Growth Angiogenesis 41 mTOR Inhibition is a Novel Approach for Blocking Angiogenesis VEGF mAb PDGF VEGF TKI PDGFR-b VEGFR mTOR PI3K Protein Synthesis Akt VHL HIF1/2 Tumor mTOR Hypoxic Stress Genes Angiogenic Growth Factors Vascular Cell Growth Angiogenesis 42 mTOR Inhibition May Enhance the Antitumor Effects of Targeted Therapies Growth Factor mAb TKI Growth factor inhibitors target either the growth factor or the receptor on the cell surface PI3K mTOR inhibitors target cancer cell growth downstream of growth factor receptors Akt Combining an mTOR inhibitor with a growth factor receptor inhibitor may be a more effective strategy for cancer treatment mTOR Protein Synthesis Cell Growth & Proliferation Bioenergetics mTOR inhibitors may be effective in patients that are refractory to growth factor inhibition Angiogenesis 43 mTOR Inhibition May Enhance the Antitumor Effects of Other Therapies Radiation Chemotherapy mTOR Inhibition Growth Factor Signaling Inhibitors Antiestrogens Antiangiogenics 44 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 45 Summary Rationale 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 46
