Breast Cancer Targeting: Hippo, a pathway too big to hide. Stuart Aaronson, M.D. Icahn School of Medicine at Mount Sinai
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1 Breast Cancer Targeting: Hippo, a pathway too big to hide Stuart Aaronson, M.D. Icahn School of Medicine at Mount Sinai
2 DISCLOSURES I am a consultant for Aileron Therapeutics, Inc. and R-Pharm.
3 Outline: Selective Cancer Targeting Some initial examples of biologically targeted cancer therapies. Introduction to the Hippo pathway and its role in cancer including a new oncogenic mechanism. Potential for Hippo targeted therapies in breast cancer and other tumor types.
4 GROWTH FACTOR RTK PIP3 PIP3 RAS SOS Grb2 P P p85 RAS Akt P PDK1 p110 PI3K Raf P MEK P ERK BAD P P NFK-B FKHR P P MDM2 P GSK3 P p70s6k PROLIFERATION CELL SURVIVAL PROLIFERATION PROTEIN SYNTHESIS CELL SURVIVAL Tumor-specific activating mutations
5 Targeted Therapy Agents that selectively target pathways important to tumors, optimally sparing normal cells May or may not lead directly to cell death Examples: PDGFR, ERBB2/HER2
6 Discovery years Clinical Translation Match of v-sis product and PDGF (Doolittle et al, Science) Isolation of PDGFR alpha gene (Matsui et al, PNAS) in vivo PDGF expression induces sarcomas in mice (Pech et al, PNAS) autocrine PDGF/PDGFR autocrine loop in human sarcoma (Fleming et al,oncogene) PDGFR alpha mab increases survival in sarcoma patients (Tap et al, Lancet).
7 Gene Discovery Relation to Cancer 1985 Relation to Prognosis Pre-clinical Development Clinical Trials We isolated an amplified erbb related receptor gene designated as erbb2/her-2/neu from a human breast cancer Clinical Application
8 Trastuzumab (Herceptin) Mechanism of Action:
9 Gene Discovery Relation to Cancer 2005 Relation to Prognosis Pre-clinical Development Clinical Trials Herceptin in combination with chemotherapy reduces recurrence of early stage breast cancer Clinical Application
10 Trastuzumab- Adjuvant (NEJM 2005)- 50% Reduction of Recurrence
11 Oncogene targeted therapies in cancer Target(s) Cancer drug Disease HER2/ ERBB2 EGFR VEGF PDGFR alpha ABL, PDGFR, KIT EGFR EGFR VEGFR, PDGFR, RET PDGFR, FLT3, KIT, VEGFR BRAF Monoclonal antibodies Trastuzumab (Herceptin) Cetuximab (Erbitux) Bevacizumab (Avastin) Olaratumab (Lartuvo) Small molecules Imatinib (Gleevec) Gefitinib (Iressa) Erlotinib (Tarceva) Sorafenib (Nexavar) Sunitinib (Sutent) Vemurafenib (Zelboraf) Breast cancer Colorectal cancer Colorectal cancer, NSCLC Soft tissue sarcomas CML, GIST NSCLC NSCLC RCC, HCC GIST, RCC Metastatic Melanoma NSCLC Mantle Cell, CLL ALK Crizotinib (Xalkori) BTK Ibrutinib (Imbruvia) Met/VEGFR2 Cabozantinib (Cometriq) Medullary thyroid BCL2 Ventoclax (Venclexta) CCL CDK4/6 Palbocilib (Ibrance); ribociclib (Kisqali); ER+ metastatic Abemaciclib (Verzenio) Breast Cancer
12 The Hippo Pathway at a Glance Negative growth regulator in normal tissue growth/homeostasis. Counteracts cell proliferation and motility through inhibition of TEAD/YAP transcription complex. Deregulation of the Hippo pathway Known mechanisms include NF2 or LATS2 inactivation; YAP amplification/overexpression; GNAQ or GNA11 oncogenic mutations. leads to increased cell proliferation, cell motility, and tumor survival Affects key drivers of cancer initiation and progression, and metastasis as shown in a transgenic animal model of Hepatocellular Carcinoma (HCC) Hepatocellular carcinoma development following YAP induction in a transgenic murine model: Forced expression of YAP for 2 months starting at 3 weeks after birth (A) or at birth (B). Valero et al. J Hepatocellular Carcinoma (2015)
13 The Mammalian Hippo Pathway Qi Zhou et al. Circ Res. 2015;116:
14 TEAD Luciferase Activity Hippo pathway mutant tumor cells show constitutively upregulated TEAD/YAP transcriptional activity T MCF10A MESO1017 H2373 MESO25 (+) Serum (-) Serum 211H 0 Low High Low High Low High Low High Low High Low High
15 dntead4 EV TEAD Reporter Luciferase Activity Hippo pathway mutant tumor cells are dependent on TEAD/YAP transcriptional activity for proliferation in culture T MCF10A MESO1017 H2373 MESO25 211H 0 dntead T MCF10A MESO1017 H2373 MESO25 211H
16 A small molecule screen identifies the tankyrase inhibitor, XAV939, as a novel inhibitor of TEAD transcriptional activity
17 XAV939 specifically inhibits growth of Hippo deregulated tumor/transformed cells in 2D/3D assays
18 Relative AMOT levels Tankyrase inhibitors stabilize AMOT family members which sequester YAP A 293T H2373 AMOT Tubulin AMOTL2 Tubulin B CTR XAV CHX(hrs) AMOT Tubulin CHX(hrs) CTR XAV C Input AMOT IgG 10% IP XAV939 AMOT YAP D Input YAP 10% IP IgG XAV939 YAP AMOT
19 Relative TEAD Luciferase activity Relative TEAD Luciferase activity Tankyrase knockdown acts like XAV939 to inhibit TEAD/YAP transcription and Hippo deregulated tumor cell growth A B Tankyrase 1-2 ß-actin Tankyrase 1-2 ß-actin C 293T D H2373 shctr shtnks1-2 shctr shtnks1-2
20 Targeting Hippo Pathway Deregulated Transcription in Cancer TNKS inhibitors GPCR TNKS1/2 NF2 G-protein AMOT MST1/2 YAP SAV1 AMOT AMOT YAP YAP LATS1/2 SCF ßTRCP Cytoplasmic Retention MOB1 YAP P Free YAP YAP YAP YAP YAP P YAP Ub P Ub Ub Proteasomal Degradation YAP TEAD1-4 Cell growth Cytoplasmic Retention Gene expression nucleus
21 Summary l: Targeting Hippo pathway deregulation in human cancers Hippo pathway deregulated tumors exhibit high TEAD/YAP transcriptional activity independent of cell density or serum. Hippo pathway deregulation confers proliferative properties to tumor cells. Antagonizing TEAD/YAP transcription by genetic manipulations specifically impairs proliferation of Hippo pathway deregulated tumor cells with lesions in the canonical Hippo pathway. TNKS inhibitors stabilize AMOTs leading to YAP cytosolic sequestration, decreased TEAD/YAP transcription and growth inhibition specifically of Hippo deregulated tumor cells(troilo et al, Oncotarget 2016).
22 p53 gain of function (GOF) mutants P53 missense mutations comprise the majority of p53 loss of function mutations (>40% of human tumors). Initially such mutations were thought to confer a dominant negative function. However, over the past 20 years ago, accumulating evidence indicates that these mutations also confer a gain of function- increased proliferation, invasiveness, motility, drug resistance. Multiple mechanisms have been implicated including increased signaling through various receptors, effects on mitochondrial activities, and/or interactions with transcription factors. These interactions have been reported to involve other p53 family members, SREBP, NF-Y, VDR, ETS2, YAP, or NRF2. Whether different p53 missense mutations exhibit the same or different GOFs is not clear. Various therapeutic strategies are being explored in efforts to restore wild type p53 function.
23 Tumor cells depend on p53 GOF mutants for proliferation a MDA- MB-231 p53 mutant cells p53 null cells MDA- MB-468 U373MG SF295 HCC193 SK-BR-3 HCC1395 U138MG SK-MEL-2 SK-LMS-1 H1299 shscr shp53
24 DNTEAD4 inhibits TEAD/YAP transcription and proliferation of p53/hippo mutant Human Tumor Cells
25 Tankyrase inhibitors also target p53/hippo tumor cells A p53/hippo mutant tumor cells p53/other GOF mutant tumor cells p53 -/- B MDA- 468 HCC- HCC- SK- SK- 193 SF295 U MLS-1 MEL-2 H1299 DMSO XAV939 10µM C XAV939 10µM TNKS1/2 AMOTL2 YAP TAZ ß actin
26 TCGA analysis reveals that p53/hippo mutant breast cancers exhibit increased TEAD/YAP transcription and decreased patient survival
27 Targeted in vivo growth inhibition of p53/hippo mutant tumors by a new inhibitor
28 New inhibitor specifically antagonizes different mechanisms of Hippo deregulation in tumor cells
29 High frequency of Hippo pathway deregulation in human breast cancer
30 Summary ll: Targeting Hippo pathway deregulation in human cancers Hippo pathway deregulation confers proliferative and invasive properties to human tumor cells. A class of p53 GOF mutations present in >10% of human tumors activate TEAD/YAP transcription and are dependent on this transcription for growth and motility. p53/hippo mutant tumors can be identified by precision medicine based molecular diagnostics. Tankyrase inhibitors stabilize AMOT family members, which sequester YAP independent of phosphorylation to inhibit Hippo pathway deregulation by different oncogenic mechanisms. Hippo pathway deregulation plays a greater role than has been appreciated in human malignancies, making further efforts to therapeutically target such tumors highly warranted.
31 Acknowledgements Lab members: Davide Esposito* Albino Troilo* Rachel Garibsingh* Erica Benson* Martina Kracikova Sathish Mungamuri Pam Cheung Rui Qiao* Shen Yao* Agustin Cardenas* Collaborators: Jian Jin, Mount Sinai Poulikos Poulikakos, Mount Sinai Marek Mlodzik, Mount Sinai Funding Sources: NCI, NICHD, BCRF, Pfizer CTI, PCF
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