Ehm Patrick, Grottke Astrid, Bettin Bettina, Jücker Manfred
Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Institute of Biochemistry and Signal Transduction, Center for Experimental Medicine, University Medical Center Hamburg-Eppendorf, Martinistr. 52, 20246 Hamburg, Germany.
Cell Signal. 2022 May;93:110301. doi: 10.1016/j.cellsig.2022.110301. Epub 2022 Mar 5.
Acute lymphoblastic leukemia is the most common cause of cancer-related death in children and, especially for patients in a high-risk group, still represents a poor prognosis. The PI3K/AKT/mTOR signaling pathway has been identified as a frequently constitutively activated switching point in the disease of ALL. Despite the knowledge of the therapeutic importance of the signaling pathway, the results of clinically effective treatment strategies have so far been extremely sobering. In particular, monotherapy approaches represent a major problem with regard to cell resistance. In this work, the PI3K/AKT/mTOR signaling pathway was examined as a therapeutic target for the treatment of childhood acute lymphoblastic leukemia (ALL) with a new therapeutic approach to avoid cell resistance. Therefore, we used a combined therapeutic approach with inhibitors directed against AKT (MK2206), mTOR (RAD001) and the most prominent and aberrantly activated tyrosine kinase. In case of BCR-ABL-positive B-ALL cells we used a combination with the classic inhibitor Imatinib and in case of MLL-AF4-positive B-ALL cells we used a combination with Quizartinib (directed against FLT3). We show, in particular compared to the monotherapies, a highly significant inhibition of the growth of these cells after this new specific triple combination therapy. Furthermore, we show that inhibiting AKT alone leads to a feedback mechanism and an upregulation of the phosphorylation of a number of receptor-tyrosine-kinases. After isoform-specific knockdown of the three AKT isoforms in ALL cells we identified that especially ErbB2/Her2 is most strongly phosphorylated in cells with AKT2 knockdown. AKT isoform 1 and 2 knockdown cells show, in contrast to AKT isoform 3 knockdown cells, a weak proliferation and are presumably kept alive among others by the increased phosphorylation of the receptor-tyrosine-kinase ErbB2. This work provides first indications for a new combination therapy of B-ALL cells, which is directed against AKT, mTOR and a predominantly highly activated kinase.
急性淋巴细胞白血病是儿童癌症相关死亡的最常见原因，尤其是对于高危组患者，其预后仍然很差。PI3K/AKT/mTOR信号通路已被确定为急性淋巴细胞白血病（ALL）疾病中经常组成性激活的转换点。尽管了解该信号通路的治疗重要性，但迄今为止，临床有效治疗策略的结果却非常令人沮丧。特别是，单一疗法在细胞耐药性方面存在重大问题。在这项工作中，PI3K/AKT/mTOR信号通路作为治疗儿童急性淋巴细胞白血病（ALL）的治疗靶点进行了研究，采用了一种新的治疗方法以避免细胞耐药性。因此，我们使用了一种联合治疗方法，使用针对AKT（MK2206）、mTOR（RAD001）以及最突出且异常激活的酪氨酸激酶的抑制剂。对于BCR-ABL阳性的B-ALL细胞，我们将其与经典抑制剂伊马替尼联合使用；对于MLL-AF4阳性的B-ALL细胞，我们将其与针对FLT3的quizartinib联合使用。我们发现，特别是与单一疗法相比，这种新的特异性三联联合治疗后，这些细胞的生长受到高度显著的抑制。此外，我们还表明，单独抑制AKT会导致一种反馈机制，并上调多种受体酪氨酸激酶的磷酸化。在ALL细胞中对三种AKT异构体进行亚型特异性敲低后，我们发现，特别是在AKT2敲低的细胞中，ErbB2/Her2的磷酸化最为强烈。与AKT异构体3敲低的细胞相比，AKT异构体1和2敲低的细胞增殖较弱，可能是通过受体酪氨酸激酶ErbB2磷酸化增加等方式维持存活。这项工作为针对AKT、mTOR和一种主要高度激活的激酶的B-ALL细胞新联合治疗提供了初步迹象。
