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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
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