基因亚型
基因敲除
多发性骨髓瘤
蛋白激酶B
PI3K/AKT/mTOR通路
癌症研究
生物
细胞培养
免疫学
信号转导
细胞生物学
遗传学
基因
作者
Claudia Hofmann,Thorsten Stühmer,Nadine Schmiedl,Reinhard Wetzker,Anja Mottok,Andreas Rosenwald,Christian Langer,Josip Zovko,Manik Chatterjee,Hermann Einsele,Ralf C. Bargou,Torsten Steinbrunn
摘要
Summary Constitutive phosphatidylinositide 3‐kinase ( PI 3K) signalling has been implicated in multiple myeloma ( MM ) pathophysiology and is regarded as an actionable target for pharmacological intervention. Isoform‐specific PI 3K inhibition may offer the most focused treatment approach and could result in greater clinical efficacy and reduced side effects. We therefore performed isoform‐specific knockdown of PIK 3 CA , PIK 3 CB , PIK 3 CD , and PIK 3 CG to analyse their individual contributions to MM cell survival and downstream signalling. In addition, we tested the effectivity of the novel PI 3K isoform‐specific inhibitors BYL ‐719 ( PIK 3 CA ), TGX ‐221 ( PIK 3 CB ), CAL ‐101 ( PIK 3 CD ), and CAY 10505 ( PIK 3 CG ). We found the PIK 3 CA isoform to be of paramount importance for constitutive Akt activity in MM cells, and – in contrast to inhibition of other class I isoforms – only the blockade of PIK 3 CA was sufficient to induce cell death in a sizeable subgroup of MM samples. Furthermore, pharmacological PIK 3 CA inhibition in combination treatments of BYL ‐719 and established anti‐myeloma agents resulted in strongly enhanced MM cell death. Our data thus clearly indicate therapeutic potential of PIK 3 CA inhibitors and support their clinical evaluation in multiple myeloma.
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