mtor e le altre vie di trasduzione del segnale: Implicazioni cliniche Giampaolo Tortora

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1 mtor e le altre vie di trasduzione del segnale: Implicazioni cliniche Giampaolo Tortora Cattedra di Oncologia Medica UOC Oncologia Medica du Facoltà di Medicina e Chirurgia e Azienda Ospedaliera Universitaria Integrata Verona

2 HER-dependent signalling pathways IGF-1R MET VEGF I3K HIF1 ER Ciardiello F & Tortora G, New England J Medi 2008

3 mtor integrates the signals of nutrients and growth factors Glucose Glucose GLUT 1 Aminoacid AT AT AMK TSC1 TSC2 I3K Akt Growth Signaling mtor senses availability of amino acids, metabolic fuel, and energy Nutrients and energy stores are essential for protein synthesis, cell growth, proliferation, and survival LAT mtor mtor activation can increase the expression of nutrient transporters rotein Synthesis mtor activation supports growth and survival by increasing cell access to nutrients and metabolic fuels Cell Growth & roliferation Angiogenesis Bioenergetics

4 mtor is a key machinery integrating the 3 pillars of growth: proliferation, angiogenesis and nutrient availability (bioenergetics) roliferation/growth Angiogenesis Bioenergetics

5 mtor pathway and inhibitors Dancey, J. Nat. Rev. Clin. Oncol. 7, (2010);

6 RAAMYCIN INTERACTIONS WITH mtor/fkb12 Rapamycin and FKB12 create a drug-receptor complex that interacts with mtor (Binding site to Raptor) (Binding site to E4B1/eIF4E) mtor RAAMYCIN RAA FKB12 mtor inhibition by rapamycin lasts for 5 days

7 mtorc1 and mtorc2 Laplante M and Sabatini DM, Celll 2012

8 mtor athway is deregulated by mutations in cancer EGF IGF Growth Signaling Nutrients Cancer Cell Ras TEN I3K TSC1 Akt TSC2 mtor rotein Synthesis VEGF Abl ER Ras Normal cell growth, proliferation, and metabolism are maintained by a number of mtor regulators 1,2 Regulators of mtor activity mtor activating mtor deactivating Deregulation of mtor can result in loss of growth control and metabolism 1,3 Mutations in the mtor pathway have been linked to specific cancers 4 Cell Growth & roliferation Angiogenesis Bioenergetics Averous and roud. Oncogene ;25(48): Mamane et al. Oncogene. 2006;25(48): Ellisen. Cell Cycle. 2005;4(11):

9 mtor athway is Deregulated in Breast Cancer Breast p-akt, 42% I3K, 18% 26% TEN, 15% 41% HER2, 30% 36%

10 Tortora G, J Natl Cancer Inst, 2012 Mechanisms of resistance to anti-her2 agents in breast cancer Mechanisms of resistance Alterations in binding sites or RTK domain Overexpression of alternative ErbB ligands/ receptors dimerization Dimerization/interaction with other structurally unrelated receptors Loss of downstream controllers Activation of downstream signaling pathways Other factors MUC4 p95 HER2, ECD mutations of TK domain Factors involved EGFR-HER2; HER2-HER3 etc. ErbB ligands (TGFa, EGF, HB-EGF, Heregulin etc.) IGF1-R MET TEN I3K-Akt MEK MAK/Erk mtor Notch Microenvironment Chemokine receptors and Integrins Metabolism Host-related factors Stem cells

11 Mechanisms of SERM Resistance Cell Survival TKI AB IGFR I3-K EGFR/HER2 TKI SOS RAS RAF MoAb Increased upstream signaling through EGFR and/or IGF-IR AI SERD T E2 lasma Membrane ER Cytoplasm CCI Akt RAD ER ER ERE p160 p90 RSK CB Basal Transcription Machinery MAK MEK ER Target Gene Transcription Nucleus Cell Growth Increased signaling through I3-K pathway Change in co-activators of ER From Johnston CCR

12 mtor transduces the signal triggered by E2 activation

Dual mtor and Aromatase Inhibition Induces Apoptosis in Breast Cancer Models Apoptotic Cells, % 25 20 15 <.

13 Dual mtor and Aromatase Inhibition Induces Apoptosis in Breast Cancer Models Apoptotic Cells, % <.05 (Friedman test) mtor Inhibitor (nm) 100 nm AI 500 nm AI Modified from Boulay et al. Clin Cancer Res. 2005;11:

14 mtor, obesity, insulin and aging Laplante M and Sabatini DM, Celll 2012

15 Absolute change in histoscore from baseline to day 15 for cyclin D1, gr, ps6-235, and ps6-240 in the letrozole and letrozole-plus-everolimus arms. Subgroup of patients with higher level of mtor activity (ps6k) at baseline had a higher RR (82% vs 60%). Baselga J et al. JCO 2009;27:

16 HER3 ENGAGED IN SIGNALING Campbell M.R: et al., Clin Cancer Res; 16: , 2010

17 Signal through class I I3Ks Di Cosimo & Baselga. Clin Cancer Res 2009;15:5017 9

18 Aberrancies in the I3K/AKT/mTOR pathway by breast cancer subtype Hernandez-Aya LF and Gonzales Angulo AM The Oncologist, 16: , 2011

showed a relatively poor antiproliferative response to letrozole alone but

19 Biomarker analysis: I3-Kinase Exploring the relationship between IK3CA mutation and Ki67, the small number of exon 9 allosteric domain mutants showed a relatively poor antiproliferative response to letrozole alone but a good response to letrozole plus everolimus Baselga J et al. JCO 2009;27:

20 Feedback loops in mtor pathway and inhibitors Dancey, J. Nat. Rev. Clin. Oncol. 7, (2010);

21 Inhibition of mtorc1 and mtorc2 Laplante M and Sabatini DM, Celll 2012

22 I3K/mTOR inhibitors being investigated for treatment of HR-positive advanced breast cancer Shtivelband MI, The Breast (2013),

23 IK3CA Genotype and a IK3CA Mutation-Related Gene Signature and Response to Everolimus and Letrozole in ER ositive Breast Cancer Relative change in % Ki67 from baseline to day 15 by treatment arm. Loi S et al., LoS ONE 8(1) 2013

24 Increase of activated EGFR/HER2 dimers in tamoxifen-resistant breast cancer cells Knowlden et al., Endocrinology 2003

25 The mtor pathway is functionally linked to ErbB/HER and VEGF Growth factors IGF-1, VEGF, ErbB, etc I3-K Oxygen, energy, and nutrients TEN Akt/KB Ras/Raf, Abl, ER VEGF TSC2 TSC1 HIF-1 Ras/Raf pathway kinases mtor S6K1 4E-B1 S6 rotein production X X X elf-4e Cell growth Angiogenesis

26 Cross-Talk Between Signal Transduction and Endocrine athways Growth factor Estrogen lasma membrane IGFR EGFR / HER2 Letrozole ER Cell survival Akt I3-K p90 RSK SOS RAS RAF MAK MEK Cytoplasm ER ER p160 CB Basal transcription machinery Cell growth Nucleus ERE ER target gene transcription Adapted from Johnston S. Clin Cancer Res. 2005;11:889S-899S.

27 hosphoproteome analysis identifies the mtor effector p70s6k1 as a specific biomarker for lapatinib resistance Vasquez-Martin A., Annals of Oncology 19: , 2008

hase III Study W2301: vinorelbine + trastuzumab everolimus in trastuzumab-resistant and taxanepretreated HER2+ advanced breast cancer 2008 2009 2010 2011 2012 2013 2014 572 pts HER2-overexpressing,

28 hase III Study W2301: vinorelbine + trastuzumab everolimus in trastuzumab-resistant and taxanepretreated HER2+ advanced breast cancer pts HER2-overexpressing, locally advanced or metastatic advanced breast cancer, prior taxane therapy and resistant to trastuzumab* S C Randomize R E 1:1 E N N=572 <21 days prior to Day 1 Stratification by prior lapatinib (Yes vs No) Everolimus 5.0 mg p.o. daily Vinorelbine 25 mg/m 2 Days 1, 8, 15 Trastuzumab 2 mg/kg Days 1, 8, 15 lacebo po daily Vinorelbine 25 mg/m 2 Days 1, 8, 15 Trastuzumab 2 mg/kg Days 1, 8, 15 1 cycle = 21 days * Trastuzumab resistance defined as progression on adjuvant trastuzumab 12 months of last infusion, or progression while on or 4 weeks of receiving last dose of trastuzumab for metastatic disease FS Survival ORR CBR Safety K Biomarkers

29 Garcia-Garcia et al Clin Cancer Res; 18(9); The simultaneous blockade of both I3K/Akt/mTOR and ERK pathways obtained by combining lapatinib with INK-128 acts synergistically in inducing cell death and tumor regression in breast cancer models refractory to anti-her2 therapy

Mechanisms of Resistance to. Lisa A. Carey, M.D. University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center

Mechanisms of Resistance to. Lisa A. Carey, M.D. University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center Mechanisms of Resistance to Hormonal Therapy Lisa A. Carey, M.D. University of North Carolina at Chapel Hill Lineberger Comprehensive Cancer Center Antagonizing Estrogen Dependent Growth Premenopausal