Burke Russell T, Meadows Sarah, Loriaux Marc M, Currie Kevin S, Mitchell Scott A, Maciejewski Patricia, Clarke Astrid S, Dipaolo Julie A, Druker Brian J, Lannutti Brian J, Spurgeon Stephen E
Knight Cancer Institute, Oregon Health and Science University, Portland, OR.
Oncotarget. 2014 Feb 28;5(4):908-15. doi: 10.18632/oncotarget.1484.
Agents that target B-cell receptor (BCR) signaling in lymphoid malignancies including idelalisib (GS-1101) and fostamatinib which inhibit the delta isoform of PI3 kinase (PI3Kd) and spleen tyrosine kinase (Syk) respectively have shown significant clinical activity. By disrupting B-cell signaling pathways, idelalisib treatment has been associated with a dramatic lymph node response, but eradication of disease and relapse in high risk disease remain challenges. Targeting the BCR signaling pathway with simultaneous inhibition of PI3Kd and Syk has not yet been reported. We evaluated the pre-clinical activity of idelalisib combined with the novel and selective Syk inhibitor GS-9973 in primary peripheral blood and bone marrow Chronic Lymphocytic Leukemia (CLL) samples. Both PI3Kd and Syk inhibition reduced CLL survival and in combination induced synergistic growth inhibition and further disrupted chemokine signaling at nanomolar concentrations including in bone marrow derived and poor risk samples. Simultaneous targeting of these kinases may significantly increase clinical activity.
在包括idelalisib（GS - 1101）和fostamatinib在内的淋巴恶性肿瘤中，分别抑制PI3激酶δ亚型（PI3Kd）和脾酪氨酸激酶（Syk）的靶向B细胞受体（BCR）信号传导的药物已显示出显著的临床活性。通过破坏B细胞信号通路，idelalisib治疗与显著的淋巴结反应相关，但根除疾病和高危疾病复发仍然是挑战。同时抑制PI3Kd和Syk靶向BCR信号通路的情况尚未见报道。我们评估了idelalisib与新型选择性Syk抑制剂GS - 9973联合用于原发性外周血和骨髓慢性淋巴细胞白血病（CLL）样本的临床前活性。PI3Kd和Syk的抑制均降低了CLL的存活率，联合使用在纳摩尔浓度下诱导了协同生长抑制，并进一步破坏了趋化因子信号传导，包括在骨髓来源的样本和高危样本中。同时靶向这些激酶可能会显著提高临床活性。
