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11/11/11 Molecular pathways in breast cancer Elgene Lim. M.D., Ph.D. Women’s Cancers Program Dana-‐Farber Cancer InsCtute This is not what this talk is about 1 11/11/11 Overview • • • • Common themes in intracellular signalling in cancer HER2+ -‐ HER2/PI3K/AKT signaling ER+ -‐ Hormone signaling Triple NegaCve ! BRCA 1 & 2 mutant – DNA repair pathway • Others ! Stromal pathways: VEGF and HIF signaling ! Apoptosis pathways ! Tumor IniCaCng cells and Epithelial Mesenchymal TransiCon IntroducCon and Themes 2 11/11/11 LimitaCons of current approaches to cancer therapy • Empiric approach to choice of chemotherapy • Toxicity due to relaCvely non-‐selecCve targeCng • Recent paradigm shi0 ! TargeCng oncogenic pathways and idenCfying predicCve biomarkers ! Altering the tumor niche ! ShiZing the balance between apoptosis and survival ! TargeCng the cancer stem cell • Key hurdles ! OZen ineffecCve alone ! Obtaining effecCve in vivo doses, isoform specificity ! IdenCficaCon of appropriate biomarkers/ appropriate subgroups ! AcquisiCon of therapeuCc resistance and relapse 3 11/11/11 Acquired CapabiliCes of Cancer RaConal targets for therapy Hanahan & Weinberg. Cell 2011 Intracellular networks in cancer cells Hanahan & Weinberg. Cell 2011 4 11/11/11 Signalling: systems or discrete pathways? Cross Talk Func.onal redundancy Oncogenic AddicCon Feedback loops • • • Majority of cancers Require targeCng of mulCple pathways • Minority of cancer • TargeCng the archilles heel Basis of resistance Response to targeted tx is modest unless they are administered concomitantly with other modali8es TargeCng the hallmarks of cancer Hanahan & Weinberg. Cell 2011 5 11/11/11 Intracellular signalling pathways HER2 signalling Signalling Cascade Ligand RTKs Dimerization Intracellular SIgnaling Gene activation Effector mechanisms Outcomes EGF ARG EGFR Ras/ Raf/ MEK Cyclin D1/2 HER Wnt IGF1-R IRS/ SHC PI3K/ AKT/ mTOR E2 Frizzled/ LRP5/6 GSK/ β-Cat/ APC ER MYC Bcl 2 VEGF Metabolism Cell growth Ins/ IGF1 NRG β-Cat/ TCF ERE HIF Survival/ Apoptosis ProliferaCon DifferenCaCon Angiogenesis MigraCon 6 11/11/11 HER2 and inter-‐related signalling pathways Overexpression DimerizaCon Morrow et al. Breast Can Res 2009 TargeCng the EGFR family Monoclonal anCbodies Ab-‐cytotoxic conjugate Tyrosine Kinase Inhibitors Alvarez et al. JCO 2010 7 11/11/11 UpregulaCon of HER3 and resistance to anC-‐HER2 therapies HER2 blockade Feedback loop HER3 upregulaCon = + Cross talk Resistance Abramson & Arteaga. Clin Cancer Res 2011 PI3K/mTOR/Akt pathway Ras/Raf/MAPK pathway 8 11/11/11 MulCple aberraCons lead to PI3K pathway acCvaCon S6K-‐IRS1 Feedback loop ê Sites of muta8on/dele8on that result in aberrant ac8va8on PI3KCA ac*va*ng muta*on Uterus 30% Breast 25% Colon 15% Bladder 15% Di Cosimo & Baselga. Clin Can Res 2009 mTOR regulates cell proliferaCon and metabolism in response to environmental factors Alvarez et al. JCO 2010 9 11/11/11 Subtype specific PI3K pathway aberraCon PIK3CA AKT1 PDK1 PTEN PTEN INPP4B RAS/RAF P53 mut mut amp mut protein loss del mut mut Breast 339/1261 27/1008 27/129 46/121 (26.9%) (2.6%) (20.9%) 6/209 (2.3%) 2/406 (total) (22.7%) Breast 101/305 6/232 16/79 4/131 10/69 HR+ (33.1%) (2.6%) (23.2%) (3.4%) (14.5%) Breast 24/98 HER2+ (24.5%) Breast 21/262 TNBC (8%) Ovarian Endometrial 0/75 0/111 2/332 2/332 (0.6%) (0.6%) 73/246 3/150 (30%) (2%) Concept of pathway aberraCon Highlighted > 20% Not included: PIK3CA amp 5/19 (26.3%) 2/15 (13.3%) Rare Rare 0/33 0/41 4/132 (3%) 20/76 (26%) 25/110 2/18 (11%) 11/21 (52%) ≈ 40% ≈ 50% ≈ 20% (0.5%) Rare (24.6%) 14/23 Rare (60.9%) 12/22 ≈ 60% ≈ 20% ≈ 8% (38%) 18/73 (63.6%) 12/428 90/132 (2.8%) (68%) 44/206 9/96 (21%) (9%) Unpublished data, SU2C collaborators TargeCng the PI3K pathway PotenCally overcomes feedback acCvaCon of PI3K with mTOR inhibiCon alone PKI 587 Current agents target primarily p110α isoform 10 11/11/11 Feedback Loops Feedback activation following Pi3K inhibition Reciprocal activation of MEK and PI3K pathways following inhibition PI3K inhibitor + MEK inhibitor trials underway in SU2C O Brien et al. Clin Can Res 2010 Rexer et al. Clin Can Res 2009 Current PI3K pathway inhibitors in clinical trials Hernandez-‐Aya & Gonzalez-‐Angulo.. Oncologist 2011 11 11/11/11 Ras/Raf/MAPK pathway Roberts & Der. Oncogene 2008 Ras mutaCons in human cancer Ac8va8ng muta8ons: impair intrinsic GTPase ac8vity, RAS accumulate in ac8ve GTP bound form. Approx 30% human cancers. Cell context and level of expression determine func8onal consequence. Schubbert S et al. NRC 2007 12 11/11/11 IGF1 signalling in human cancer Breast Prostate Colon Liver Melanoma GBM Mesothelioma Myeloma Sachdev & Yee. Mol Ther 2007 Hormone receptor pathway 13 11/11/11 Growth pathways in ER+ cells Aromatase Inhibitors Tamoxifen Fulvestrant Co-‐targe.ng pathways Hormonal Tx + EGFR inhibitor HER2 inhibitor PI3K inhibitor IGF-‐1R inhibitor Survival ProliferaCon DifferenCaCon Johnston. Clin Breast Can 2009 Regulatory network in ER-‐HER2+AR+ breast cancer AR Androgen metabolism SRD5A1, UGT2B28, etc Wnt7b PI3K Nuclear !-catenin AR AR ERBB3/2 p-Akt p27Kip p21Cip Targets Ni et al, Cancer Cell 2011 14 11/11/11 DNA repair pathway BRCA1 mutaCon and cancer • 220 kDa nuclear protein • Tumour suppressor gene • Loss of funcCon mutaCons predispose to cancer ! Majority truncaCng nonsense + frameshiZ mutaCons ! Asso genomic instability Lifetime risk BRCA1 General Population • Basal/Triple negaCve Phenotype Breast Ca 65% 10% Ovarian Ca 40% 1-2% • MutaCons are rare in sporadic tumours • PreventaCve strategies: ProphylacCc mastectomy and ovariectomy 15 11/11/11 BRCA and DNA repair BRCA1 • Broad cellular role • Signaling of DNA damage ! Phosphorylated by kinases central to DNA damage response, ATM/ATR and CHK • DNA repair ! homologous recombina8on ! nucleoCde-‐excision repair BRCA2 • Restricted to DNA recombinaCon and repair processes ! homologous recombina8on; RegulaCon of RAD51 acCvity SyntheCc lethality: targeCng a weakness in DNA repair 16 11/11/11 Resistance to carboplaCn through BRCA2 reversion mutaCon Ashworth. Cancer Res 2008 Stromal signaling pathways Angiogenesis/VEGF signaling 17 11/11/11 TargeCng the tumor micro-‐enviroment Hanahan & Weinberg. Cell 2011 AnC-‐angiogenic strategies 18 11/11/11 TargeCng the HIF pathway Kaelin W. Cancer 2009 Apoptosis pathway 19 11/11/11 ApoptoCc Pathways Intrinsic pathway Extrinsic pathway Cytokines Death ligand Microenvironment GlucocorCcoids Cell surface receptors Death receptor Bcl-‐2 family proteins MOMP Cyt C APAF-‐1 Caspases Signaling complex Cellular stress Hypoxia DNA damage Cell demoliCon zymogens Substrate deprivaCon Cleavage of DNA, cellular proteins Phagocytosis RegulaCon of apoptosis BH3-‐ mimeCc BH3-‐only proteins More potent killers Pro-‐ survival proteins BH3-‐only proteins More restricted killers Cragg et al, Nat Rev Can 2009 20 11/11/11 Bcl-‐2 (B-‐cell Lymphoma-‐2) Family Pro-‐ apoptoCc (BH3-‐only) Pro-‐survival Bad Bcl-‐2 Bim Bcl-‐xL Pro-‐apoptoCc (mulC-‐domain) Puma Noxa Bcl-‐w Mcl-‐1 A1 Bax/Bak Bax and Bak are restrained in healthy cells Pro-‐ apoptoCc (BH3-‐only) Pro-‐survival Pro-‐apoptoCc (mulC-‐domain) Bad Bcl-‐2 Bim Bcl-‐xL Puma Bcl-‐w Noxa Mcl-‐1 A1 Bax/Bak 21 11/11/11 BH3-‐only proteins are acCvated by discrete cues Cytokine withdrawal Pro-‐ apoptoCc (BH3-‐only) Pro-‐survival Steroid p53 Bad Bim Bcl-‐2 DNA damage hypoxia Ca2+ flux, Taxol, UV Pro-‐apoptoCc (mulC-‐domain) Puma Bcl-‐xL Noxa Bcl-‐w Mcl-‐1 A1 Bax/Bak NeutralisaCon of anC-‐apoptoCc proteins releases Bax/Bak Cytokine withdrawal Pro-‐ apoptoCc (BH3-‐only) Pro-‐survival Pro-‐apoptoCc (mulC-‐domain) Steroid p53 Bad Bcl-‐2 DNA damage hypoxia Ca2+ flux, Taxol, UV Bim Bcl-‐xL Puma Bcl-‐w Noxa Mcl-‐1 A1 Bax/Bak Apoptosis 22 11/11/11 Tumour cells acquire lesions at mulCple levels Cytokine withdrawal Pro-‐ apoptoCc (BH3-‐only) Pro-‐survival Steroid p53 Bad Bim Bcl-‐2 DNA damage hypoxia Ca2+ flux, Taxol, UV Pro-‐apoptoCc (mulC-‐domain) Puma Bcl-‐xL Noxa Bcl-‐w Mcl-‐1 A1 Bax/Bak TargeCng prosurvival proteins to overcome chemoresistance Cytokine withdrawal Pro-‐ apoptoCc (BH3-‐only) Pro-‐survival Pro-‐apoptoCc (mulC-‐domain) DNA damage hypoxia Ca2+ flux, Taxol, UV Steroid p53 Bad Bim Puma Bcl-‐w Noxa Drug Bcl-‐2 Bcl-‐xL Mcl-‐1 A1 Bax/Bak Apoptosis 23 11/11/11 Expression of pro-‐survival proteins in breast cancer • HER2+ BC is correlated with high levels of Mcl-‐1 ! Mcl-‐1 is downstream target of acCvated EGFR and PI3K signaling ! HercepCn sensiCzes cells to apoptosis by reducing Mcl-‐1 expression ! Mcl-‐1 overexpression confers resistance to drug induced apoptosis • Estradiol induces ! Bcl-‐2 (pro-‐survival) expression in MCF7 cells via 2 EREs located with its coding region (Perillo, MCB 00) ! Puma (pro-‐apoptoCc) downregulaCon in ER+ cell lines (Bur, Onc 11) Establishment of orthotopic breast cancer xenograZs Bcl-‐2 IHC TNBC TNBC HER2+ 24 11/11/11 CombinaCon therapy results in tumor response and increased survival in triple negaCve xenograZs High Bcl-‐2 Mid Mcl-‐1 Low Puma High Noxa High Bcl-‐2 Mid Mcl-‐1 Mid Puma Mid Noxa High Bcl-‐2 Mid Mcl-‐1 High Puma Low Noxa Oakes et al, PNAS 2011 CombinaCon therapy has no effect on tumor xenograZs with low BCL-‐2 25 11/11/11 Pathways in Tumor IniCaCng Cells Epithelial Mesenchymal TransiCon Mammary development meets cancer genomics Old paradigm New model Basal-‐like Claudin-‐low BRCA1 Normal-‐like Gene signature Others? HER2 Luminal B Basal-‐like Luminal A (BRCA1) HER2 Luminal B Luminal A Lim E et al. Nature Med 2009 26 11/11/11 Models of heterogeneity in solid cancers Clonal selec.on model CSC model Reya et al. Nature 2001 Breast cancer tumor iniCaCng cells Minimum no of cells to produce cancer >100,000 200 Al-‐Hajj et al. PNAS 2003 27 11/11/11 ImplicaCons of the cancer stem cell hypothesis on cancer therapy Cure Clinical recurrence Failure of primary therapy CSC targeCng strategies DifferenCaCon therapy (APML) Reya et al. Nature 2001 Wnt/β-‐Catenin Signalling Pathway IncassaC et al. Breast Cancer Research 2010 28 11/11/11 Paracrine sCmulaCon of Wnt/β-‐Catenin Pathway in stem cells EMT and Tumor iniCaCng cell phenotype • EMT is a process by which cells acquire molecular alteraCons that facilitate dysfuncConal cell–cell adhesive interacCons and juncCons, as well as a more spindle-‐shaped morphology. • Claudin-‐low subtype is characterized by high expression of EMT markers • EMT promotes cancer cell progression and invasion into the surrounding microenvironment, and • EMT promotes the expression of stem cell and TIC markers, and promotes self-‐renewal capability. • Developmental signaling pathways that play a role in mammary carcinogenesis and stem cell biology include Notch, PI3-‐AKT, Wnt, Hedgehog and p53. 29 11/11/11 Epithelial-‐Mesenchymal transiCon Foubert et al. Breast Cancer Research 2010 Pathways & inhibitors in TICs and EMT Stem cells and TICs • Notch • Wnt/β-‐Catenin γ Secretase inhibtors Wnt inhibitors EMT • TGF-‐β • Snail, Slug and Twist 30 11/11/11 QuesCons 31
