Combination of PKCδ Inhibition with Conventional TKI Treatment to Target CML Models.
Combination of PKCδ Inhibition with Conventional TKI Treatment to Target CML Models.
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DOI：
10.3390/cancers13071693
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发表时间：
2021-04-02
期刊：
影响因子：
5.2
通讯作者：
Mary D
中科院分区：
文献类型：
--
作者：
Muselli F;Mourgues L;Morcos R;Rochet N;Nebout M;Guerci-Bresler A;Faller DV;William RM;Mhaidly R;Verhoeyen E;Legros L;Peyron JF;Mary D
酪氨酸激酶抑制剂（TKI）伊马替尼是第一种靶向治疗，通过抑制断点簇区域-Abelson鼠白血病病毒癌基因同源物（BCR-ABL）显示出对慢性髓细胞白血病（CML）的临床疗效，该区域是该疾病的原因。另外两代TKI已成功地用于伊马替尼，为越来越多的伊马替尼耐药CML患者提供了额外的治疗方案。然而，这些临床方法虽然非常有效，但由于其每日施用而产生许多不想要的副作用。当疾病在分子水平上不再可检测时，尝试停止TKI，不幸的是，超过一半的病例会复发。这突出了不可检测的白血病细胞的存在，被认为是TKI不敏感的白血病干细胞（LSC）。因此，似乎有必要确定LSC中的新生化途径，其靶向将使TKI的再致敏成为可能。本文提供的结果表明，靶向蛋白激酶Cδ（PKCδ）途径是消除LSC的有效替代方案。已经提出了与酪氨酸激酶抑制剂（TKI）治疗相关的信号传导通路阻断的许多组合用于根除慢性髓性白血病（CML）中的白血病干细胞（LSC），但目前没有一种在临床上可用。由于靶向蛋白激酶Cδ（PKCδ）已被证明可以消除实体瘤中的癌症干细胞（CSC），因此我们评估了PKCδ抑制与TKI联合治疗CML细胞的疗效。我们观察到，通过药理学抑制剂、基因沉默或使用表达显性阴性（DN）或组成型活性（CA）PKCδ亚型的K562 CML细胞抑制PKCδ，明确指出PKCδ是干性调节因子BMI 1表达的调节因子。因此，PKCδ的抑制损害白血病细胞的克隆形成和细胞增殖。K562和LAMA-84 CML细胞系中的PKCδ靶向明显增强了由任何TKI触发的凋亡反应。通过增加caspase-9和caspase-3的活化和显著降低Bcl-xL Bcl-2家族成员的表达，观察到了强烈的协同作用。抑制PKCδ并不改变BCR-ABL磷酸化，但通过下调BMI 1表达作用于癌基因下游，降低克隆形成。PKCδ抑制与任何TKI一样有效地干扰原代CML CD 34+和BCR-ABL转导的健康CD 34+细胞的克隆形成，但不影响健康CD 34+细胞的分化。LTC-IC实验指出，PKCδ抑制强烈降低祖细胞/LSC频率。总之，这些结果表明，靶向PKCδ与常规TKI组合可能是影响CML细胞的新治疗机会。
The tyrosine kinase inhibitor (TKI) imatinib was the first targeted therapy to show clinical efficacy against chronic myeloid leukemia (CML) through inhibition of the breakpoint cluster region–Abelson murine leukemia viral oncogene homolog (BCR-ABL), which is responsible for the disease. Two other generations of TKIs have succeeded imatinib, offering additional therapeutic solutions for a growing number of patients with imatinib-resistant CML. However, these clinical approaches although very effective, generate many unwanted side effects because of their daily administration. Attempts to stop TKI when the disease is no longer detectable at the molecular level, unfortunately result in relapses in more than half of cases. This highlights the presence of undetectable leukemia cells, recognized as leukemic stem cells (LSCs) that are TKI insensitive. It therefore appears necessary to identify new biochemical pathways in LSCs, the targeting of which would make re-sensitization to TKIs possible. The results presented here demonstrate that targeting the protein kinase Cδ (PKCδ) pathway represents a valid alternative for LSC elimination. Numerous combinations of signaling pathway blockades in association with tyrosine kinase inhibitor (TKI) treatment have been proposed for eradicating leukemic stem cells (LSCs) in chronic myeloid leukemia (CML), but none are currently clinically available. Because targeting protein kinase Cδ (PKCδ) was demonstrated to eliminate cancer stem cells (CSCs) in solid tumors, we evaluated the efficacy of PKCδ inhibition in combination with TKIs for CML cells. We observed that inhibition of PKCδ by a pharmacological inhibitor, by gene silencing, or by using K562 CML cells expressing dominant-negative (DN) or constitutively active (CA) PKCδ isoforms clearly points to PKCδ as a regulator of the expression of the stemness regulator BMI1. As a consequence, inhibition of PKCδ impaired clonogenicity and cell proliferation for leukemic cells. PKCδ targeting in K562 and LAMA-84 CML cell lines clearly enhanced the apoptotic response triggered by any TKI. A strong synergism was observed for apoptosis induction through an increase in caspase-9 and caspase-3 activation and significantly decreased expression of the Bcl-xL Bcl-2 family member. Inhibition of PKCδ did not modify BCR-ABL phosphorylation but acted downstream of the oncogene by downregulating BMI1 expression, decreasing clonogenicity. PKCδ inhibition interfered with the clonogenicity of primary CML CD34+ and BCR-ABL-transduced healthy CD34+ cells as efficiently as any TKI while it did not affect differentiation of healthy CD34+ cells. LTC-IC experiments pinpointed that PKCδ inhibition strongly decreased the progenitors/LSCs frequency. All together, these results demonstrate that targeting of PKCδ in combination with a conventional TKI could be a new therapeutic opportunity to affect for CML cells.
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影响因子：
23.9
作者：
Lagadinou, Eleni D.;Sach, Alexander;Callahan, Kevin;Rossi, Randall M.;Neering, Sarah J.;Minhajuddin, Mohammad;Ashton, John M.;Pei, Shanshan;Grose, Valerie;O'Dwyer, Kristen M.;Liesveld, Jane L.;Brookes, Paul S.;Becker, Michael W.;Jordan, Craig T.
通讯作者：
Jordan, Craig T.
影响因子：
3.8
作者：
Chen Z;Forman LW;Williams RM;Faller DV
通讯作者：
Faller DV
影响因子：
20.3
作者：
Fang, GF;Kim, CN;Bhalla, KN
通讯作者：
Bhalla, KN
影响因子：
51.1
作者：
Mahon, Francois-Xavier;Rea, Delphine;Rousselot, Philippe
通讯作者：
Rousselot, Philippe
影响因子：
82.9
作者：
Kreso, Antonija;van Galen, Peter;O'Brien, Catherine A.
通讯作者：
O'Brien, Catherine A.