Unmet medical needs in NSCLC treatment

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(MORe) Barcelona Cancer Therapeutics Innovation Group (CTIG), New

1 Unmet medical needs in NSCLC treatment R Rosell Catalan Institute of Oncology, Badalona, Barcelona Molecular Oncology Research Foundation (MORe) Barcelona Cancer Therapeutics Innovation Group (CTIG), New York XIV Congreso Nacional de Oncología Médica Salamanca 23 October 2013

2 Coactivation of PI3K/Akt/mTOR and Ras signaling pathways occurs frequently in advanced cancer and is associated with adverse patient outcome (well established) Crosstalk between oncogenic pathways induces continual MEK- ERK signaling which maintains a reconfigured pattern inducing EMT-TF reprogramming (well established) Therefore, almost all patients with advanced cancer eventually develop resistance to current available cytotoxic and targeted therapies (well established) Genotyping is not enough for the patient s expectations and deciphering crosstalk could be crucial for synthetic lethal therapies Contributions: Bivona et al. Nature 2011 (NFKBIA - I ) Zhang et al. Nature Genetics 2012 (AXL) Rosell. Lancet Oncology 2012 (EURTAC) Rosell et al. NEJM 2013 (MED12) Rosell, Bivona & Karachaliou. The Lancet 2013 (BIM) Rosell & Karachaliou. Nat Rev Clin Oncol (mtor)

3 BIOMARKERS Intrinsic apoptopic pathway MCL1, FBW7, Noxa, BIM KRAS-mutant tumours: Bcl-X L, BIM Extrinsic apoptopic pathway Trail, BIM, FOXO3, mir-494 GALNT14, FUT3/6, SIX1 DR4/DR5, PEA15 MAPK/AKT/AMPK FOXO3a, BIM, MED23 VEGF-A, T790M KRAS-mutant tumours: FOXO3, LKB1, IGF1R NOTCH3: HES1, DUSP1, NUMB TP53: MDM2, iaspp AXL:AXL, GAS6, RELA, NFκB IL-6:IL-6, JAK, STAT3 TGF-β:TGF-βR2, MED12 EMT phenotype HEDGEHOG: GLI1, SOX2, SOX9, CXCR4, FGF19, apkcl/λ, mtor/s6k1 camp PKA: PKA, PDE4A/D POTENTIAL THERAPEUTIC COMBINATIONS Vorinostat plus ABT-737; gefitinib plus ABT-737 ABT-263 (navitoclax) plus selumetinib TIC10 plus EGFR TKIs Dulanermin, drozitumab Dulanermin, Drozitumab EGFR TKIs +Taxanes Erlotinib+Bevacizumab (BELIEF) Selumetinib/trametinib; selumetinib/trametinib plus triciribine; selumetinib/trametinib plus paclitaxel; phenformin/metformin; IGF1R inhibitors plus selumetinib/trametinib EGFR TKIs plus γ-secretase inhibitor BRAF inhibitors plus MDM2 inhibitors plus iaspp inhibitors EGFR TKIs plus AXL inhibitors EGFR TKIs plus AXL inhibitors; EGFR TKIs plus pan-jak inhibitors EGFR TKIs plus TGF-β inhibitors EGFR TKIs plus apkcl/λ inhibitors EGFR TKIs plus mtor inhibitors EGFR TKIs plus PDE4 inhibitors Rosell, Bivona, Karachaliou. Lancet. 2013

Stromal HGF confers EGFR TKI resistance and induces interreceptor crosstalk with integrin- 4, Eph2, CDCP1, AXL and JAK1 (Gusenbauer, Vlaicu & Ullrich.

4 Stromal HGF confers EGFR TKI resistance and induces interreceptor crosstalk with integrin- 4, Eph2, CDCP1, AXL and JAK1 (Gusenbauer, Vlaicu & Ullrich. Oncogene 2013) Also, HGF is present in melanoma stromal cells and correlates with poor response. A similar resistance mechanism was shown in a subset of BRAF mutant colorectal and glioblastoma cell lines (Straussman et al. Nature 2012)

Minimum 8,8 mm 2 tumor and stroma tissue for

FFPE block following pathology assessment if

5 Minimum 8,8 mm 2 tumor and stroma tissue for the RNA analysis Cuts of tissue mandatory 4 µm or more (5 cuts if block cannot be sent) Further tissue can be cut as required from the FFPE block following pathology assessment if the whole block is sent BELIEF trial. N Karachaliou, C Teixido

6 Shin et al. JNCI 2013 Rosell. NEJM 2013 Kanda et al. Cancer Res 2013

7 MAPK activity and EMT-TF reprogramming in the time course of tumor progression. A late EMT-TF reprogramming is dependent on continual MAPK signaling Caramel Cancer Cell 2013

8 Wang et al. PNAS 2013 EGFRvIII induces secretion of IL-6 which activates gp130, generating a paracrin loop which promotes activation of EGFR in neighboring cells (Inda et al. Genes Dev 2010) Gao et al. J Clin Investigation 2007

EGFRvIII triggering nuclear transport of EGFRvIII,

9 Zadeh et al. Cancer Cell 2013 Steder et al. Cancer Cell 2013 Activated WT EGFR phosphorylates EGFRvIII triggering nuclear transport of EGFRvIII, and enhanced phosphorylation of STAT3 (Fan et al. Cancer Cell 2013)

10 NFKBIA encoding I B the major negative regulator of NF B Erlotinib treated EGFR mutant NSCLC Bredel et al. NEJM 2010 Bivona et al. Nature 2011

11 IKK α IKK β BIM Rosell, Bivona, Karachaliou. Lancet. 2013

12 Nuclear factor of -light polypeptide gene enhancer in B-cells (NF B) a transcription factor activated by EGFR mutations (including EGFRvIII) and other oncogenes AXL/GAS6, mtorc2 and the non-cannonical NOTCH pathway activate NF B AXL also activates IL-6 and STAT3 MYC-driven tumors can activate NF B (PDK1-PLK1-MYC) - PLK1 inhibitor blocks mtor inhibition-induced MYC activation (Tan et al. Cancer Cell 2010) EGFR T790M mutation-mediated acquired resistance an unmet medical need Crosstalk of mtorc1 with Beclin, Bcl2 and BIM Cross-regulation DGK -PDE4A/D-PKA-cAMP-mTORC1 Genomic fluidity (Wip1/PPM1D-LINE-1/APOBEC) EURTAC BREC/SCAT BELIEF GOAL - Serial rebiopsy study - AXL inhibitor trial EUCROSS NVALT Platelets/plasma (EML4-ALK) EGFR mutants (cdna) CTCs

13 EURTAC cutoff January 2013 Rosell et al. Lancet Oncology 2012

14 T790M mutation is present in up to 62-82% of cases at time of clinical progression to erlotinib (Arcila CCR 2011; Su et al. JCO 2012) Allelic dilution makes it difficult to identify T790M by direct sequencing. A low frequency of expression of the mutant allele HER2 T798M (3%) was sufficient to confer drug resistance (Rexer et al. CCR 2013) Pre-existing T790M mutation found in 27% of EGFR-mutant patients by massively parallel sequencing (Querings et al. PLoS ONE 2011), in 31.5% by MALDI-TOF MS (Su et al. JCO 2012), in 35% by PCR-PNA assay (Rosell, Molina et al. CCR 2011), in 38% by SARMS (Maheswaran et al. NEJM 2008), and related to shorter PFS to gefitinib or erlotinib (Maheswaran et al. NEJM 2008; Rosell et al. CCR 2011; Su et al. JCO 2012) Pre-existing EGFR T790M found in 65% of EURTAC samples. Also, 50% found in the BELIEF and GOAL studies

15 G1: Erlotinib and T790M present (n=34) G2: Erlotinib and T790M absent (n=16) G3: Chemotherapy and T790M present (n=28) G4:Chemotherapy and T790M absent (n=17) G2 G G3 G1 Patients at risk EURTAC cutoff January 2013

16 TRAIL DR4/DR5 GPCR AC BIM BIM TRAIL Rosell, Bivona, Karachaliou. Lancet. 2013

17 EGFR mutant NSCLC patients ABT-263/Erlotinib TORCi/SOCE agonists (IGR1)Corcoran et al. Science Transl Med 2013 H1650 (ABT-263/gefitinib) Cragg et al. PLoS MED 2007 DGKa/PDE4/PKA/ERK/mTORC1 EURTAC cutoff January 2013

18 Rosell & Karachaliou. Nat.Rev.Clin.Oncol. 2013

19 LKB1 EGFR L858R/T790M (H1975) DGKa PDE4A/D AMPK TSC1/TSC2 Rheb PI3K/AKT mtorc1 ERK Metformin KRAS/LKB1 (A549) Atg13 ULK1/2 Atg101 FIP200 1) Autophagosome initiation AKT ABT-737/ABT-263 H1650 2) Nucleation Ambra1 p150 Beclin1 Atg14L CIII-PI3K/Vps34 Bcl2 Rubicon Bcl-XL BIM 4) Delivery & Degradation Atg12 Atg16L Atg7 Atg5 Atg10 3) Elongation p62 U U NBR1 LC3 LC3-II LC3-II Courtesy of Niki Karachaliou Maes et al. Trends in Molecular Medicine 2013 Wirawan et al. Cell Death and Disease. 2010

In the TKI-sensitive HCC827 cells (but not in TKI-resistant H1975 cells),

binding, disruption of Beclin 1/Rubicon binding, increased Beclin 1/VPS34

20 In the TKI-sensitive HCC827 cells (but not in TKI-resistant H1975 cells), erlotinib led to EGFR dephosphorylation, disruption of EGFR/Beclin 1 binding, disruption of Beclin 1/Rubicon binding, increased Beclin 1/VPS34 binding, decreased Beclin 1/Bcl-2 binding, and increased Beclin 1-associated VPS34 kinase activity. Also HCC827 cells but not H1975 cells show LC3-II conversion and P62 degradation after erlotinib treatment. Wei et al. Cell 2013

21 Afatinib TAK-1 LKB1 Ca ++ CaMKKα/β PTEN L858R/T790M (H1975) PI3K Akt PHLPP AR FKBP5 Enobosarm SARMs RAS RAF AMPK PRKA2 TSC1/TSC2 Rheb Amino-acid starvation mtorc1 STIM1 (H1975, A549) PDE4A/D DGKa Hypoxia ERK Rap1 GTPase DOCK4 Sirolimus/SOCE agonists ULK1/2 FIP200 SOCE Atg13 Atg101 Akt autophagy VEGFA/VEGFR1 LC3 & Beclin1 mrna & IHC) Vasculogenic mimicry LC3 I Soluble form Ambra1 Beclin1 CIII-PI3K/Vps34 Atg12 Atg16L Atg7 Atg5 Atg10 LC3 II (H1650) ABT-737/ABT-263 Lipidated form Rubicon Bcl2 Mcl-1 Bcl-XL Modified from Rosell, Bivona, Karachaliou. Lancet 2013 Atg9 autophagy BIM-EL apoptosis LC3-II p62 U U NBR1 Autophagosome

22 Cunningham & Ruggero. Cancer Discovery 2013 PLK1 inhibitor blocks mtor inhibitor-induced MYC activation (Tan et al. Cancer Cell 2010) A number of genes implicated in ESC are upregulated in HEK-PDK1 cells and HEK-MYC cells: SOX2, LIN28B, SALL4, EZH2. Others such as EPCAM, ALDHIA, S100A4 are also upregulated and considered markers of CSCs (Tan et al. Cancer Discovery 2013)

23 Well-characterized panel of cell lines for determination of clinically relevant markers H1975(EGFR del /T790M) rolipram sensitive PDE4D Our findings (DGKa/PDE4/PKA/ ERK/mTORC1) A549 (KRAS/LKB1) rolipram sensitive PDE4D Our findings DGKa/PDE4/PKA/ERK H460 (KRAS/LKB1) rolipram resistant PDE4D intermediate / PDE4A (N Karachaliou) NOTCH3/HES1/ERK1. Sensitive to erlotinib/secretase inhibitors H1650 (EGFR del/ BIM) sensitive to ABT-263/gefitinib DGKa/PDE4/PKA/ ERK/mTORC1, rolipram partly sensitive IGR1 (BRAF melanoma) BIM resistant to VEM ( ERK/ mtorc1 ) Sensitive to VEM/ABT-263, or a TORC inhibitor (Corcoran et al. Science Trans Med 2013) Pullamsetti et al. Oncogene 2013 Dominguez et al. Cancer Discovery 2013

Rolipram reduces proliferation in H1975 cell line Serum-starved (0%, 0.1% and 0.5% FBS, normoxia) 1,2 1 0,8 Viability 0,6 0,4 H1975 0% FBS 1,2 1 0,8 Viability 0,6 0,4 H1975 0.

24 Rolipram reduces proliferation in H1975 cell line Serum-starved (0%, 0.1% and 0.5% FBS, normoxia) 1,2 1 0,8 Viability 0,6 0,4 H1975 0% FBS 1,2 1 0,8 Viability 0,6 0,4 H % FBS 0,2 0, Rolipram μm Rolipram μm Molina & Bertran-Alamillo H % 1,2 1 0,8 Viability 0,6 0,4 0, Rolipram μm Pullamseti et al. Oncogene 2013

25 BIM high/mtor low-intermediate: mos=35.8m BIM high/mtor high: mos=20.3m BIM low/mtor low-intermediate: mos=17.7m BIM low/mtor high: mos=25.1m N. Karachaliou and A. Droz

26 A potential algorithm for directing EGFR TKI therapy in EGFR mutant NSCLC BIM mrna expression BIM BIM Low High erlotinib gefitinib afatinib + Bcl2i PDE4i Taxanes High T790M model mtor model T790M present T790M absent mtor high mtor low afatinib/pemetrexed Afatinib/bevacizumab Courtesty N Karachaliou erlotinb gefitinib afatinib erlotinb gefitinib afatinib + mtori+soce agonists or PLK i metformin or 2DG erlotinb gefitinib afatinib

27 Conclusions Only BIM mrna expression is an independent marker of both PFS and OS in the EURTAC study mtorc1 modulates survival in NSCLC expressing high BIM (Karachaliou et al.) BIM and mtor essential markers for adequate treatment of NSCLC patients with EGFR mutations, and probably other subclasses of lung cancer

28 Acknowledgements Ana Drozdowskyj, Miguel Angel Molina, Andres Felipe Cardona, Ana Giménez-Capitán, Jordi Bertran-Alamillo, Clara Mayo, Jordi Codony, Radj Gervais,Teresa Moran, Margarita Majem, Enriqueta Felip, Enric Carcereny, Felipe Cardenal, Ramon Palmero, Ruth Porta, Joaquim Bosch, Santiago Ponce-Aix, Ana Estival, Rosario Garcia-Campelo, Santiago Viteri, Amaya Gasco, Daniela Morales-Espinosa, Cristina Teixido, Jose Luis Ramirez, Miquel Taron, Carlos Camps, Manuel Cobo, Manuel Domine, Isabel Bover, Mariano Provencio, Guillermo Lopéz-Vivanco, Dolores Isla, Bartomeu Massuti, Alain Vergnenegre, Solange Peters, Rolf Stahel, Jia Wei, Baroui Liu, Silvia Garcia-Roman, Roger Estrada, Trever Bivona, Niki Karachaliou Spanish Lung Cancer Group (SLCG) French Lung Cancer Group European Thoracic Oncology Group (ETOP) Comprehensive Cancer Center of Drum Tower Hospital Nanjing Cancer Therapeutics Innovation Group (CTIG) Pangaea Biotech S.L, Quirón Dexeus University Hospital Pivotal, Madrid Institut Químic de Sarrià (IQS) / Grup d Enginyeria Molecular (GEM)

II CANCER CELL SIGNALING PATHWAYS CONFERENCE

II CANCER CELL SIGNALING PATHWAYS CONFERENCE AN IN DEPTH LOOK AT LUNG, MELANOMA, GLIOBLASTOMA, BREAST, HEAD & NECK SQUAMOUS CELL CANCERS Fundació Institut d Investigació en Ciències de la Salut Germans