Jensen Holly A, Bunaciu Rodica P, Varner Jeffrey D, Yen Andrew
School of Chemical and Biomolecular Engineering, Cornell University, Ithaca, NY, United States.
Department of Biomedical Sciences, Cornell University, Ithaca, NY, United States.
Cell Signal. 2015 Aug;27(8):1666-75. doi: 10.1016/j.cellsig.2015.03.014. Epub 2015 Mar 26.
The multivariate nature of cancer necessitates multi-targeted therapy, and kinase inhibitors account for a vast majority of approved cancer therapeutics. While acute promyelocytic leukemia (APL) patients are highly responsive to retinoic acid (RA) therapy, kinase inhibitors have been gaining momentum as co-treatments with RA for non-APL acute myeloid leukemia (AML) differentiation therapies, especially as a means to treat relapsed or refractory AML patients. In this study GW5074 (a c-Raf inhibitor) and PP2 (a Src-family kinase inhibitor) enhanced RA-induced maturation of t(15;17)-negative myeloblastic leukemia cells and rescued response in RA-resistant cells. PD98059 (a MEK inhibitor) and Akti-1/2 (an Akt inhibitor) were less effective, but did tend to promote maturation-uncoupled G1/G0 arrest, while wortmannin (a PI3K inhibitor) did not enhance differentiation surface marker expression or growth arrest. PD98059 and Akti-1/2 did not enhance differentiation markers and have potential, antagonistic off-targets effects on the aryl hydrocarbon receptor (AhR), but neither could the AhR agonist 6-formylindolo(3,2-b)carbazole (FICZ) rescue differentiation events in the RA-resistant cells. GW5074 rescued early CD38 expression in RA-resistant cells exhibiting an early block in differentiation before CD38 expression, while for RA-resistant cells with differentiation blocked later, PP2 rescued the later differentiation marker CD11b; but surprisingly, the combination of the two was not synergistic. Kinases c-Raf, Src-family kinases Lyn and Fgr, and PI3K display highly correlated signaling changes during RA treatment, while activation of traditional downstream targets (Akt, MEK/ERK), and even the surface marker CD38, were poorly correlated with c-Raf or Lyn during differentiation. This suggests that an interrelated kinase module involving c-Raf, PI3K, Lyn and perhaps Fgr functions in a nontraditional way during RA-induced maturation or during rescue of RA induction therapy using inhibitor co-treatment in RA-resistant leukemia cells.
癌症的多变量性质需要多靶点治疗，激酶抑制剂占已批准的癌症治疗药物的绝大多数。虽然急性早幼粒细胞白血病（APL）患者对维甲酸（RA）治疗高度敏感，但激酶抑制剂作为与RA联合治疗非APL急性髓性白血病（AML）分化疗法的势头越来越大，尤其是作为治疗复发或难治性AML患者的一种手段。在本研究中，GW5074（一种c-Raf抑制剂）和PP2（一种Src家族激酶抑制剂）增强了RA诱导的t(15;17)阴性髓母细胞白血病细胞的成熟，并挽救了RA耐药细胞中的反应。PD98059（一种MEK抑制剂）和Akti-1/2（一种Akt抑制剂）效果较差，但确实倾向于促进成熟解偶联的G1/G0期阻滞，而渥曼青霉素（一种PI3K抑制剂）并未增强分化表面标志物表达或生长阻滞。PD98059和Akti-1/2并未增强分化标志物，并且对芳烃受体（AhR）有潜在的、拮抗的脱靶效应，但AhR激动剂6-甲酰吲哚并(3,2-b)咔唑（FICZ）也无法挽救RA耐药细胞中的分化事件。GW5074挽救了RA耐药细胞中早期CD38的表达，这些细胞在CD38表达之前表现出早期分化阻滞，而对于后期分化受阻的RA耐药细胞，PP2挽救了后期分化标志物CD11b；但令人惊讶的是，两者的组合并无协同作用。激酶c-Raf、Src家族激酶Lyn和Fgr以及PI3K在RA治疗期间显示出高度相关的信号变化，而在分化过程中，传统下游靶点（Akt、MEK/ERK）甚至表面标志物CD38的激活与c-Raf或Lyn的相关性较差。这表明，在RA诱导的成熟过程中，或者在使用抑制剂联合治疗挽救RA耐药白血病细胞的RA诱导疗法期间，涉及c-Raf、PI3K、Lyn以及可能还有Fgr的相互关联的激酶模块以非传统方式发挥作用。
