MET dysregulation is a hallmark of aggressive disease in multiple myeloma patients
Alberto Rocci
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorManuela Gambella
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorSimona Aschero
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorIleana Baldi
Unit of Biostatistics, Public Health and Epidemiology, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy
Search for more papers by this authorLivio Trusolino
Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), Candiolo (Torino), Italy
Department of Oncological Sciences, University of Torino School of Medicine, Candiolo (Torino), Italy
Search for more papers by this authorFederica Cavallo
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorFrancesca Gay
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorAlessandra Larocca
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorValeria Magarotto
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorPaola Omedè
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorGianluca Isaia
Division of Geriatric, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Torino, Torino, Italy
Search for more papers by this authorAndrea Bertotti
Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), Candiolo (Torino), Italy
Department of Oncological Sciences, University of Torino School of Medicine, Candiolo (Torino), Italy
Search for more papers by this authorAnna M. Liberati
Department of Oncohaematology, University of Perugia, Santa Maria Hospital, Terni, Italy
Search for more papers by this authorLucio Catalano
Divisione di Ematologia, Università Federico II, Napoli, Italy
Search for more papers by this authorLuca De Rosa
Haematology and Bone Marrow Transplantation Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
Search for more papers by this authorPellegrino Musto
Department of Onco-Haematology, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy
Search for more papers by this authorRoberto Vallone
Servizio di Immunoematologia e Trasfusione, DH Ematologia Azienda Ospedaliera G. Rummo, Benevento, Italy
Search for more papers by this authorAntonietta Falcone
Divisione di Ematologia, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Search for more papers by this authorDaniela Drandi
Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorMarco Ladetto
Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorPaolo M. Comoglio
Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), Candiolo (Torino), Italy
Department of Oncological Sciences, University of Torino School of Medicine, Candiolo (Torino), Italy
Search for more papers by this authorMario Boccadoro
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorCorresponding Author
Antonio Palumbo
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Correspondence: Antonio Palumbo, Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy.
E-mail: [email protected]
Search for more papers by this authorAlberto Rocci
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorManuela Gambella
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorSimona Aschero
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorIleana Baldi
Unit of Biostatistics, Public Health and Epidemiology, Department of Cardiac, Thoracic and Vascular Sciences, University of Padova, Padova, Italy
Search for more papers by this authorLivio Trusolino
Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), Candiolo (Torino), Italy
Department of Oncological Sciences, University of Torino School of Medicine, Candiolo (Torino), Italy
Search for more papers by this authorFederica Cavallo
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorFrancesca Gay
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorAlessandra Larocca
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorValeria Magarotto
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorPaola Omedè
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorGianluca Isaia
Division of Geriatric, Department of Clinical and Biological Sciences, S. Luigi Gonzaga Hospital, University of Torino, Torino, Italy
Search for more papers by this authorAndrea Bertotti
Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), Candiolo (Torino), Italy
Department of Oncological Sciences, University of Torino School of Medicine, Candiolo (Torino), Italy
Search for more papers by this authorAnna M. Liberati
Department of Oncohaematology, University of Perugia, Santa Maria Hospital, Terni, Italy
Search for more papers by this authorLucio Catalano
Divisione di Ematologia, Università Federico II, Napoli, Italy
Search for more papers by this authorLuca De Rosa
Haematology and Bone Marrow Transplantation Unit, Azienda Ospedaliera San Camillo-Forlanini, Rome, Italy
Search for more papers by this authorPellegrino Musto
Department of Onco-Haematology, IRCCS, Referral Cancer Center of Basilicata, Rionero in Vulture (Pz), Italy
Search for more papers by this authorRoberto Vallone
Servizio di Immunoematologia e Trasfusione, DH Ematologia Azienda Ospedaliera G. Rummo, Benevento, Italy
Search for more papers by this authorAntonietta Falcone
Divisione di Ematologia, Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy
Search for more papers by this authorDaniela Drandi
Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorMarco Ladetto
Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorPaolo M. Comoglio
Laboratory of Molecular Pharmacology, Institute for Cancer Research and Treatment (IRCC), Candiolo (Torino), Italy
Department of Oncological Sciences, University of Torino School of Medicine, Candiolo (Torino), Italy
Search for more papers by this authorMario Boccadoro
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Search for more papers by this authorCorresponding Author
Antonio Palumbo
Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy
Correspondence: Antonio Palumbo, Myeloma Unit, Division of Haematology, University of Torino, Azienda Ospedaliera Città della Salute e della Scienza di Torino, Torino, Italy.
E-mail: [email protected]
Search for more papers by this authorSummary
Abnormal activation of MET/HGF (Hepatocyte Growth Factor) pathway has been described in several tumours and increased HGF plasmatic levels have been detected in patients with aggressive multiple myeloma (MM). MET and HGF mRNA expression was investigated in 105 samples of purified plasma cells derived from newly diagnosed MM patients treated with bortezomib-based induction therapy. Gene expression was compared with response to therapy and clinical outcome. MET gene copy number was also evaluated. MET mRNA expression was higher in CD138+ than in CD138− cells (median 76·90 vs. 11·24; P = 0·0009). Low MET mRNA expression characterized patients with better response (complete response or very good partial response) compared to other patients (median 56·10 vs. 134·83; P = 0·0006). After a median follow-up of 50 months, patients with high MET mRNA expression displayed a worse progression-free survival (PFS; P = 0·0029) and overall survival (OS; P = 0·0023) compared to those with low MET mRNA levels. Patients with both high MET mRNA expression and high β2-microglobulin level (>5·5 mg/l) had further worse median PFS (P < 0·0001) and OS (P < 0·0001). Patients carrying 4 MET gene copies (8 out of 82, 9·8%) also had a short PFS. High MET mRNA expression identifies patients with dismal PFS and OS and the combination with high β2-microglobulin further characterizes patients with worse outcome.
References
- Börset, M., Hjorth-Hansen, H., Seidel, C., Sundan, A. & Waage, A. (1996) Hepatocyte growth factor and its receptor c-met in multiple myeloma. Blood, 88, 3998–4004.
- Cappuzzo, F., Marchetti, A., Skokan, M., Rossi, E., Gajapathy, S., Felicioni, L., Del Grammastro, M., Sciarrotta, M.G., Buttitta, F., Incarbone, M., Toschi, L., Finocchiaro, G., Destro, A., Terracciano, L., Roncalli, M., Alloisio, M., Santoro, A. & Varella-Garcia, M. (2009) Increased MET gene copy number negatively affects survival of surgically resected non-small-cell lung cancer patients. Journal of Clinical Oncology, 27, 1667–1674.
- Comoglio, P.M., Giordano, S. & Trusolino, L. (2008) Drug development of MET inhibitors: targeting oncogene addiction and expedience. Nature Review. Drug Discovery, 7, 504–516.
- Danilkovitch-Miagkova, A. & Zbar, B. (2002) Dysregulation of Met receptor tyrosine kinase activity in invasive tumors. The Journal of Clinical Investigation, 109, 863–867.
- Derksen, P.W., Keehnen, R.M., Evers, L.M., van Oers, M.H., Spaargaren, M. & Pals, S.T. (2002) Cell surface proteoglycan syndecan-1 mediates hepatocyte growth factor binding and promotes Met signaling in multiple myeloma. Blood, 99, 1405–1410.
- Durie, B.G., Harousseau, J.L., Miguel, J.S., Bladé, J., Barlogie, B., Anderson, K., Gertz, M., Dimopoulos, M., Westin, J., Sonneveld, P., Ludwig, H., Gahrton, G., Beksac, M., Crowley, J., Belch, A., Boccadaro, M., Cavo, M., Turesson, I., Joshua, D., Vesole, D., Kyle, R., Alexanian, R., Tricot, G., Attal, M., Merlini, G., Powles, R., Richardson, P., Shimizu, K., Tosi, P., Morgan, G. & Rajkumar, S.V.; International Myeloma Working Group (2006) International uniform response criteria for multiple myeloma. Leukemia, 20, 1467–1473.
- Galimi, F., Torti, D., Sassi, F., Isella, C., Corà, D., Gastaldi, S., Ribero, D., Muratore, A., Massucco, P., Siatis, D., Paraluppi, G., Gonella, F., Maione, F., Pisacane, A., David, E., Torchio, B., Risio, M., Salizzoni, M., Capussotti, L., Perera, T., Medico, E., Di Renzo, M.F., Comoglio, P.M., Trusolino, L. & Bertotti, A. (2011) Genetic and expression analysis of MET, MACC1, and HGF in metastatic colorectal cancer: response to met inhibition in patient xenografts and pathologic correlations. Clinical Cancer Research, 17, 3146–3156.
- Graziano, F., Galluccio, N., Lorenzini, P., Ruzzo, A., Canestrari, E., D'Emidio, S., Catalano, V., Sisti, V., Ligorio, C., Andreoni, F., Rulli, E., Di Oto, E., Fiorentini, G., Zingaretti, C., De Nictolis, M., Cappuzzo, F. & Magnani, M. (2011) Genetic activation of the MET pathway and prognosis of patients with high-risk, radically resected gastric cancer. Journal of Clinical Oncology, 29, 4789–4795.
- Hanamura, I., Stewart, J.P., Huang, Y., Zhan, F., Santra, M., Sawyer, J.R., Hollmig, K., Zangarri, M., Pineda-Roman, M., van Rhee, F., Cavallo, F., Burington, B., Crowley, J., Tricot, G., Barlogie, B. & Shaughnessy, J.D. Jr (2006) Frequent gain of chromosome band 1q21 in plasma-cell dyscrasias detected by fluorescence in situ hybridization: incidence increases from MGUS to relapsed myeloma and is related to prognosis and disease progression following tandem stem-cell transplantation. Blood, 108, 1724–1732.
- Hastie, T. & Tibshirani, R. (1990) Generalized Additive Models. Chapman & Hall, London, UK.
- Hideshima, T., Mitsiades, C., Tonon, G., Richardson, P.G. & Anderson, K.C. (2007) Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets. Nature Review Cancer, 7, 585–598.
- Holt, R.U., Fagerli, U.M., Baykov, V., Rø, T.B., Hov, H., Waage, A., Sundan, A. & Børset, M. (2008) Hepatocyte growth factor promotes migration of human myeloma cells. Haematologica, 93, 619–622.
- Ke, A.W., Shi, G.M., Zhou, J., Wu, F.Z., Ding, Z.B., Hu, M.Y., Xu, Y., Song, Z.J., Wang, Z.J., Wu, J.C., Bai, D.S., Li, J.C., Liu, K.D. & Fan, J. (2007) Role of overexpression of CD151 and/or c-Met in predicting prognosis of hepatocellular carcinoma. Hepatology, 49, 491–503.
- Kristensen, I.B., Christensen, J.H., Lyng, M.B., Møller, M.B., Pedersen, L., Rasmussen, L.M., Ditzel, H.J. & Abildgaard, N. (2013) Hepatocyte growth factor pathway upregulation in the bone marrow microenvironment in multiple myeloma is associated with lytic bone disease. British Journal of Haematology, 161, 373–382.
- Lennerz, J.K., Kwak, E.L., Ackerman, A., Michael, M., Fox, S.B., Bergethon, K., Lauwers, G.Y., Christensen, J.G., Wilner, K.D., Haber, D.A., Salgia, R., Bang, Y.J., Clark, J.W., Solomon, B.J. & Iafrate, A.J. (2011) MET amplification identifies a small and aggressive subgroup of esophagogastric adenocarcinoma with evidence of responsiveness to crizotinib. Journal of Clinical Oncology, 29, 4803–4810.
- Mahtouk, K., Tjin, E.P., Spaargaren, M. & Pals, S.T. (2010) The HGF/MET pathway as target for the treatment of multiple myeloma and B-cell lymphomas. Biochimica et Biophysica Acta, 1806, 208–219.
- Munshi, N.C., Anderson, K.C., Bergsagel, P.L., Shaughnessy, J., Palumbo, A., Durie, B., Fonseca, R., Stewart, A.K., Harousseau, J.L., Dimopoulos, M., Jagannath, S., Hajek, R., Sezer, O., Kyle, R., Sonneveld, P., Cavo, M., Rajkumar, S.V., San Miguel, J., Crowley, J. & Avet-Loiseau, H.; International Myeloma Workshop Consensus Panel 2. (2011) Guidelines for risk stratification in multiple myeloma: report of the International Myeloma Workshop Consensus Panel 2. Blood, 117, 4696–4700.
- Palumbo, A., Gay, F., Falco, P., Crippa, C., Montefusco, V., Patriarca, F., Rossini, F., Caltagirone, S., Benevolo, G., Pescosta, N., Guglielmelli, T., Bringhen, S., Offidani, M., Giuliani, N., Petrucci, M.T., Musto, P., Liberati, A.M., Rossi, G., Corradini, P. & Boccadoro, M. (2010a) Bortezomib as induction before autologous transplantation, followed by lenalidomide as consolidation-maintenance in untreated multiple myeloma patients. Journal of Clinical Oncology, 28, 800–807.
- Palumbo, A., Bringhen, S., Rossi, D., Cavalli, M., Larocca, A., Ria, R., Offidani, M., Patriarca, F., Nozzoli, C., Guglielmelli, T., Benevolo, G., Callea, V., Baldini, L., Morabito, F., Grasso, M., Leonardi, G., Rizzo, M., Falcone, A.P., Gottardi, D., Montefusco, V., Musto, P., Petrucci, M.T., Ciccone, G. & Boccadoro, M. (2010b) Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: a randomized controlled trial. Journal of Clinical Oncology, 28, 5101–5109.
- Podar, K., Tai, Y.T., Lin, B.K., Narsimhan, R.P., Sattler, M., Kijima, T., Salgia, R., Gupta, D., Chauhan, D. & Anderson, K.C. (2002) Vascular endothelial growth factor-induced migration of multiple myeloma cells is associated with beta 1 integrin- and phosphatidylinositol 3-kinase-dependent PKC alpha activation. The Journal of Biological Chemistry, 277, 7875–7881.
- Que, W., Chen, J., Chuang, M. & Jiang, D. (2012) Knockdown of c-Met enhances sensitivity to bortezomib in human multiple myeloma U266 cells via inhibiting Akt/mTOR activity. APMIS, 120, 195–203.
- Ross, F.M., Avet-Loiseau, H., Ameye, G., Gutiérrez, N.C., Liebisch, P., O'Connor, S., Dalva, K., Fabris, S., Testi, A.M., Jarosova, M., Hodkinson, C., Collin, A., Kerndrup, G., Kuglik, P., Ladon, D., Bernasconi, P., Maes, B., Zemanova, Z., Michalova, K., Michau, L., Neben, K., Hermansen, N.E., Rack, K., Rocci, A., Protheroe, R., Chiecchio, L., Poirel, H.A., Sonneveld, P., Nyegaard, M., Johnsen, H.E.; European Myeloma Network. (2012) Report from the european myeloma network on interphase FISH in multiple myeloma and related disorders. Haematologica, 97, 1272–1277.
- Sawada, K., Radjabi, A.R., Shinomiya, N., Kistner, E., Kenny, H., Becker, A.R., Turkyilmaz, M.A., Salgia, R., Yamada, S.D., Vande Woude, G.F., Tretiakova, M.S. & Lengyel, E. (2007) c-Met overexpression is a prognostic factor in ovarian cancer and an effective target for inhibition of peritoneal dissemination and invasion. Cancer Research, 67, 1670–1679.
- Spigel, D.R., Ervin, T.J., Ramlau, R., Daniel, D.B., Goldschmidt, J.H., Blumenschein, G.R., Krzakowski, M.J., Robinet, G., Clement-Duchene, C., Barlesi, F., Govindan, R., Patel, T., Orlov, S.V., Wertheim, M.S., Zha, J., Pandita, A., Yu, W., Yauch, R.L., Patel, P.H. & Peterson, A.C. (2011) Final efficacy results from OAM4558g, a randomized phase II study evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. Journal of Clinical Oncology, 29, (abstract 7505).
- Standal, T., Abildgaard, N., Fagerli, U.M., Stordal, B., Hjertner, O., Borset, M. & Sundan, A. (2007) HGF inhibits BMP-induced osteoblastogenesis: possible implications for the bone disease of multiple myeloma. Blood, 109, 3024–3030.
- Stein, U., Walther, W., Arlt, F., Schwabe, H., Smith, J., Fichtner, I., Birchmeier, W. & Schlag, P.M. (2009) MACC1, a newly identified key regulator of HGF-MET signaling, predicts colon cancer metastasis. Nature Medicine, 15, 59–67.
- Teofili, L., Di Febo, A.L., Pierconti, F., Maggiano, N., Bendandi, M., Rutella, S., Cingolani, A., Di Renzo, N., Musto, P., Pileri, S., Leone, G. & Larocca, L.M. (2001) Expression of the c-met proto-oncogene and its ligand, hepatocyte growth factor, in Hodgkin disease. Blood, 97, 1063–1069.
- Tjin, E.P., Groen, R.W., Vogelzang, I., Derksen, P.W., Klok, M.D., Meijer, H.P., van Eeden, S., Pals, S.T. & Spaargaren, M. (2006) Functional analysis of HGF/MET signaling and aberrant HGF-activator expression in diffuse large B-cell lymphoma. Blood, 107, 760–768.
- Trusolino, L., Bertotti, A. & Comoglio, P.M. (2010) MET signalling: principles and functions in development, organ regeneration and cancer. Nature Review. Molecular Cell Biology, 11, 834–848.
- Wader, K.F., Fagerli, U.M., Børset, M., Lydersen, S., Hov, H., Sundan, A., Bofin, A. & Waage, A. (2012) Immunohistochemical analysis of hepatocyte growth factor and c-Met in plasma cell disease. Histopathology, 60, 443–451.
- Yap, T.A., Olmos, D., Brunetto, A.T., Tunariu, N., Barriuso, J., Riisnaes, R., Pope, L., Clark, J., Futreal, A., Germuska, M., Collins, D., deSouza, N.M., Leach, M.O., Savage, R.E., Waghorne, C., Chai, F., Garmey, E., Schwartz, B., Kaye, S.B. & de Bono, J.S. (2011) Phase I trial of a selective c-MET inhibitor ARQ 197 incorporating proof of mechanism pharmacodynamic studies. Journal of Clinical Oncology, 29, 1271–1279.
Citing Literature
