Inhibition of mTOR complex 2 restrains tumor angiogenesis in multiple myeloma

Abstract

// Aurelia Lamanuzzi 1, * , Ilaria Saltarella 1, * , Vanessa Desantis 1 , Maria Antonia Frassanito 2 , Patrizia Leone 1 , Vito Racanelli 1 , Beatrice Nico 3 , Domenico Ribatti 3, 4 , Paolo Ditonno 5 , Marcella Prete 1 , Antonio Giovanni Solimando 1 , Francesco Dammacco 1 , Angelo Vacca 1 and Roberto Ria 1 1 Department of Biomedical Sciences and Human Oncology, Internal Medicine Unit G. Baccelli, University of Bari Aldo Moro Medical School, Bari, Italy 2 Department of Biomedical Sciences and Human Oncology, General Pathology Unit, University of Bari Aldo Moro Medical School, Bari, Italy 3 Department of Basic Medical Sciences, Neurosciences, and Sensory Organs, Section of Human Anatomy and Histology, University of Bari Aldo Moro Medical School, Bari, Italy 4 National Cancer Institute Giovanni Paolo II, Bari, Italy 5 Hematology Unit, Di Venere Hospital, Bari, Italy * These authors have contributed equally to this work Correspondence to: Angelo Vacca, email: angelo.vacca@uniba.it Keywords: angiogenesis; endothelial cells; multiple myeloma; mTOR; PP242 Received: June 08, 2017      Accepted: March 13, 2018      Published: April 17, 2018 ABSTRACT The mammalian Target of Rapamycin (mTOR) is an intracellular serine/threonine kinase that mediates intracellular metabolism, cell survival and actin rearrangement. mTOR is made of two independent complexes, mTORC1 and mTORC2, activated by the scaffold proteins RAPTOR and RICTOR, respectively. The activation of mTORC1 triggers protein synthesis and autophagy inhibition, while mTORC2 activation promotes progression, survival, actin reorganization, and drug resistance through AKT hyper-phosphorylation on Ser473. Due to the mTOR pivotal role in the survival of tumor cells, we evaluated its activation in endothelial cells (ECs) from 20 patients with monoclonal gammopathy of undetermined significance (MGUS) and 47 patients with multiple myeloma (MM), and its involvement in angiogenesis. MM-ECs showed a significantly higher expression of mTOR and RICTOR than MGUS-ECs. These data were supported by the higher activation of mTORC2 downstream effectors, suggesting a major role of mTORC2 in the angiogenic switch to MM. Specific inhibition of mTOR activity through siRNA targeting RICTOR and dual mTOR inhibitor PP242 reduced the MM-ECs angiogenic functions, including cell migration, chemotaxis, adhesion, invasion, in vitro angiogenesis on Matrigel ® , and cytoskeleton reorganization. In addition, PP242 treatment showed anti-angiogenic effects in vivo in the Chick Chorioallantoic Membrane (CAM) and Matrigel ® plug assays. PP242 exhibited a synergistic effect with lenalidomide and bortezomib, suggesting that mTOR inhibition can enhance the anti-angiogenic effect of these drugs. Data to be shown indicate that mTORC2 is involved in MM angiogenesis, and suggest that the dual mTOR inhibitor PP242 may be useful for the anti-angiogenic management of MM patients.