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The MET oncogene: From molecular biology to Clinical Trials Paolo M. Comoglio, MD

The MET oncogene: From molecular biology to Clinical Trials Paolo M. Comoglio, MD Institute for Cancer Research @ Candiolo, University of Turin, Medical School, Italy . P. P. P. P. MET IS A ‘MASTER GENE’ IN THE CONTROL OF INVASIVE GROWTH. Sema domain. HGF (Scatter Factor). 500 AA.

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The MET oncogene: From molecular biology to Clinical Trials Paolo M. Comoglio, MD

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  1. The MET oncogene: From molecular biology to Clinical Trials Paolo M. Comoglio, MD Institute for Cancer Research @ Candiolo, University of Turin, Medical School, Italy

  2. P P P P MET IS A ‘MASTER GENE’ IN THE CONTROL OF INVASIVE GROWTH Sema domain HGF (Scatter Factor) 500 AA MRS (PSI) G-P rich Ig like domains S-S 400 AA Kringles Protease-like Tyrosine Kinase Met (HGF Receptor)

  3. P P P P PI3K PI3K p85 p85 P P Transient MAP kinase activation (proliferation) Cell-Polarity and Morphogenesis Plexin B1 MET Integrin 6 4 CD44v6 Link to cytoskeleton GAB1 CRKL GRB2 RAS PLC GRB2 STAT SHP2 SRC Sustained MAP and PI3 kinase activation (invasion / apoptosis protection) C.Boccaccio and PM.Comoglio. Nature Rev. Cancer. 2006, 6: 637-645.

  4. MET IS A FUNCTIONAL MARKER OF CANCER STEM CELLS Human metastatic colorectal cancer Xenopatient Spheropatient Xenosphere (cancer stem cells)

  5. Xenopatients, Xenospheres and Spheropatients Xenopatient Xenosphere (cancer stem cells) Spheropatient (Secondary xenopatient) Mutations retained and passed on Response to targeted drugs retained and passed on C. Boccaccio et al., in preparation

  6. MET inhibition promotes differentiation of CRC colospheres Control JNJ inhib. Cetuximab Fibroblast conditioned medium 0% serum

  7. ACTIVATION OF THE MET-DRIVEN ‘INVASIVE GROWTH’ PROGRAMME GENERATES AN AGGRESSIVE PHENOTYPE • ONCOGENE ‘EXPEDIENCE’ • ONCOGENE ‘ADDICTION’

  8. THE CONCEPT OF ‘ONCOGENE EXPEDIENCE ‘ • Met can promote invasion and metastasis independent of the genetic lesions that caused tumour onset • Met activation is a ‘stress’ response to unfavourable microenvironment (hypoxia, radiations , inflammatory cytokines) • Met activation occurs mainly through transcriptional upregulation • Met activation is an expedience that provides a pro-survival and invasive advantage Trusolino and Comoglio., Nature Rev. Drug Discov, 2008 Nature Rev. Mol. Cell. Biol. 2010

  9. Cellular [O2] Proteasome degradation HIF Proline Hydroxylase pVHL HIF-1 (regulated) -OH   Cytoplasm Nucleus HIF-1 HIF-1 (constitutive)  P (-2619) S (-411) S (-345) A (-253) A (-32) START S (+89) A (+353) AP-1 HRE-1 HRE-2 asHRE-1 asHRE-2/ HRE-3 HRE-4 HRE-5 S (-295) Hypoxia promotes invasive growth by transcriptional activation of the MET Oncogene The MET promoter

  10. MET HIF-1a Hypoxia promotes invasive growth by transcriptional activation of the MET Oncogene CoCl2 21% O2 3% O2 Control met mRNA 28S Pennacchietti, Michieli et al. , Cancer Cell 3: 347 (2003)

  11. THE CONCEPT OF ‘ONCOGENE ADDICTION ‘ • In a limited number of cancer types, genetic lesions of Met are selected along the tumour natural history to become the driving force that maintains the transformed phenotype • Met activation is the consequence of a fixed and transmissible genetic alteration; therefore, it is characterized by chronic firing and high steady-state signalling

  12. ‘Oncogenic addiction’ to MET in tumours can be achieved by: • Amplification (e.g. gastric ca, NSCLCs and CRC mts resistant to targeted therapy) • Point mutations • hereditary and sporadic carcinomas (e.g. kidney, hepatocellular, head & neck ca. - early metastatic cancers of unknown primary origin (CUPs) Trusolino and Comoglio, Nature Rev. Drug Discov. 2008

  13. TARGET THERAPIES AGAINST MET • An adjuvant approach for a vast number of tumours: Overexpression: targeting ‘expedience’ (almost all solid tumors expressing MET) - Endpoints: PFS, OS • A front-line intervention for a limited fraction ofgenotype-specific tumours: Amplification, mutations : targeting ‘addiction’ (e.g. gastric ca., NSCLC, gefitinib-resistant NSCLCs) - Endpoints: Remission

  14. THERAPEUTIC INACTIVATION OF THE MET ONCOGENECAN BE ACHIEVED BY: Small molecules inhibiting the Tyrosine Kinase Monoclonal Antibodies

  15. RESPONSE TO MET INHIBITORS CORRELATES WITH GENE AMPLIFICATION 200 cancer l. tested Cell Line MET copy N° < 3 % ADDICTION EBC-1 5.8 MKN-45 6 GTL-16 6.1 HS746T 6.3 97 % EXPEDIENCE SNU5 5.6 NCI-H1993 5.2 Hypoxia (or HGF) PHA-665752 PHA-665752

  16. Clinical trials for MET inhibitors Inhibition of growth (reduction of tumor mass) is expected only in cancers “addicted” to MET Genetic lesions are expected in ~ 3-4 % of epithelial cancers It is mandatory to identify patiens with cancers “addicted” to MET before recruitment

  17. 111In DTPA-DN30 tumor uptake at 2h post injectionSPEC-CT scan A2780 EBC1

  18. Bardelli. et al. Cancer Discovery 2013

  19. Detection of MET-amplification by Liquid Biopsy

  20. Xenopatient-derived cancer cells display MET amplification and are sensitive to Met targeted drugs 1,4 1,2 1 0,8 cell viability % 0,6 0,4 0,2 0 NT 10 50 500 10 50 500 JNJ CRIZOTINIB

  21. Therapy with MET antibody O OH n MV-DN30 Monoclonal Antibody Monovalent, Chimeric, Stabilized • Recombinant, properly assembled and PEGylated • Bind Met (IP4) with high affinity (Kd= 0,116 nM) • Down-regulate the Met receptor from the cell surface • Induce shedding of the extracellular domain (“decoy”)

  22. S - S Ligand Ligand neutralization neutralization Inactive Inactive p125 p125 receptor receptor heterodimer heterodimer Decoy Inhibitory effects Shedding Adam 10 Γ- secretase Proteasome degradation Met Met p55 p55 p50 p50 p175 p175

  23. Exogenous administration of anti-MET DN-30 inhibits tumor growth and prevent metastasis Human Breast Carcinoma, transplanted in Athymic nu/nu mice Irrelevant Mab Mab DN30 Petrelli, A. et al., Proc. Natl.Acad Sci. US: 2006, 28, 5090-5095

  24. CHEMOTHERAPY (CDDP, 5FU) vs MET ANTIBODY TREATMENT OF EBC1 - Xenotransplants- Tumor Volume Days after injection

  25. MECHANISMS OF ACQUIRED RESISTANCE TO MET KINASE INHIBITORS • METamplification • Activatingpointmutations

  26. Amplification of MET contributes to acquired resistance to MET kinase inhibitors PHA resistant (150 nM) Wt Chromosome 7 centromere MET amplicon marker GTL16 wt

  27. P P P Some MET mutations confer resistance to MET inhibitors PHA 250 nM WT 1 2 3 4 5 6 7 8 9 M1131T V1188L L1196V V1220I S985 Y1003 D1228H (Kit) D1228N (Kit) Y1230C Y1230H M250T (Ret) a-pMet P P a-Met P Y1349 Y1356

  28. FAb DN30 treatment overcomes resistance to the MET kinase Inhibitor PHA-665752 DN30 Fab 0.4 mM Viability in 50 nM PHA EBC1 wt EBC1 PHA Resistant EBC1 Wild Type EBC1 PHA Resistant

  29. MET and Invasive Growth: • State of the art: • Scatter factors andthe receptors of the MET oncogene family (RON, ROR) are key regulators of the Invasive Growth program in cancer stem cells. • The program isactivatedby METover expression, induced by unfavourable micro-environmental conditions, such as hypoxia or ionizing radiations: (“Oncogene Expedience”). • The invasive growth program is constitutively activated in some cancers, by METamplification, mutations or autocrine loops (“Oncogene Addiction”). • The invasive growth program driven by the oncogene MET is a good target for therapy. • Resistance may occur, that may be overcome by combined treatment with s.m. inhibitors and antibodies

  30. IRCC Experimental Clinical Molecular Oncology Met and resistance S. Giordano S. Corso A. Petrelli C. Migliore Met & Stem cells C. Boccaccio F. De Bacco P. Luraghi G. Reato Ron & ROR S. Benvenuti A. Gentile L. Lazzari A. Arnesano Met & Hypoxia P. Michieli S. Pennacchietti C. Basilico Met Addiction L.Trusolino A. Bertotti F. Galimi Met Gene Therapy E. Vigna S. Cignetto R. Albano Met Signature E. Medico Met Biology L. Lanzetti Met Genetics A. Bardelli M.F. Di Renzo Plexins L.Tamagnone E. Giraudo G. Serini

  31. “Today Science, Tomorrow Medicine” IRCC: Institute for Cancer Research @ Candiolo

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