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

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