Validation of PDGFRβ and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: Preclinical efficacy of the novel, orally available inhibitor dasatinib

Addolorata Maria Luce Coluccia, Teresa Cirulli, Paola Neri, Domenica Mangieri, Maria Cristina Colanardi, Antonio Gnoni, Nicola Di Renzo, Franco Dammacco, Pierfrancesco Tassone, Domenico Ribatti, Carlo Gambacorti-Passerini, Angelo Vacca

Research output: Contribution to journalArticle

Abstract

Inhibition of multiple myeloma (MM) plasma cells in their permissive bone marrow microenvironment represents an attractive strategy for blocking the tumor/ vessel growth associated with the disease progression. However, target specificity is an essential aim of this approach. Here, we identified platelet-derived growth factor (PDGF)-receptor beta (PDGFRp) and pp60c-Src as shared constitutively activated tyrosine-kinases (TKs) in plasma cells and endothelial cells (ECs) isolated from MM patients (MMECs). Our cellular and molecular dissection showed that the PDGF-BB/PDGFRp kinase axis promoted MM tumor growth and vessel sprouting by activating ERK1/2, AKT, and the transcription of MMEC-released proangiogenic factors, such as vascular endothelial growth factor (VEGF) and interleukin-8 (IL-8). Interestingly, pp60c-Src TK-activity was selectively induced by VEGF in MM tumor and ECs, and the use of small-interfering (si)RNAs validated pp60c-Src as a key signaling effector of VEGF loop required for MMEC survival, migration, and angiogenesis. We also assessed the antitumor/vessel activity of dasatinib, a novel orally bioactive PDGFRp/Src TK- inhibitor that significantly delayed MM tumor growth and angiogenesis in vivo, showing a synergistic cytotoxicity with conventional and novel antimyeloma drugs (ie, melphalan, prednisone, bor- tezomib, and thalidomide). Overall data highlight the biologic and therapeutic relevance of the combined targeting of PDGFRp/c-Src TKs in MM, providing a framework for future clinical trials.

Original languageEnglish
Pages (from-to)1346-1356
Number of pages11
JournalBlood
Volume112
Issue number4
DOIs
Publication statusPublished - Aug 15 2008

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ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

Cite this

Coluccia, A. M. L., Cirulli, T., Neri, P., Mangieri, D., Colanardi, M. C., Gnoni, A., Di Renzo, N., Dammacco, F., Tassone, P., Ribatti, D., Gambacorti-Passerini, C., & Vacca, A. (2008). Validation of PDGFRβ and c-Src tyrosine kinases as tumor/vessel targets in patients with multiple myeloma: Preclinical efficacy of the novel, orally available inhibitor dasatinib. Blood, 112(4), 1346-1356. https://doi.org/10.1182/blood-2007-10-116590