Outlook on PI3K/AKT/mTOR inhibition in acute leukemia.

Molecular and cellular therapies Pub Date : 2015-03-20 eCollection Date: 2015-01-01
Lars Fransecky, Liliana H Mochmann, Claudia D Baldus
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Abstract

Technological advances allowing high throughput analyses across numerous cancer tissues have allowed much progress in understanding complex cellular signaling. In the future, the genetic landscape in cancer may have more clinical relevance than diagnosis based on tumor origin. This progress has emphasized PI3K/AKT/mTOR, among others, as a central signaling center of cancer development due to its governing control in cellular growth, survival, and metabolism. The discovery of high frequencies of mutations in the PI3K/AKT/mTOR pathway in different cancer entities has sparked interest to inhibit elements of this pathway. In acute leukemia pharmacological interruption has yet to achieve desirable efficacy as targetable downstream mutations in PI3K/AKT/mTOR are absent. Nevertheless, mutations in membrane-associated genes upstream of PI3K/AKT/mTOR are frequent in acute leukemia and are associated with aberrant activation of PI3K/AKT/mTOR thus providing a good rationale for further exploration. This review attempts to summarize key findings leading to aberrant activation and to reflect on both promises and challenges of targeting PI3K/AKT/mTOR in acute leukemia. Our emphasis lies on the insights gained through high-throughput data acquisition that open up new avenues for identifying specific subgroups of acute leukemia as ideal candidates for PI3K/AKT/mTOR targeted therapy.

Abstract Image

急性白血病中PI3K/AKT/mTOR抑制的研究进展
技术的进步使得高通量分析跨越众多的癌症组织,使得理解复杂的细胞信号有了很大的进展。在未来,癌症的遗传景观可能比基于肿瘤起源的诊断更具临床意义。这一进展强调了PI3K/AKT/mTOR等作为癌症发展的中心信号中心,因为它控制着细胞生长、存活和代谢。不同癌症实体中PI3K/AKT/mTOR通路高频突变的发现引发了抑制该通路元件的兴趣。在急性白血病中,由于PI3K/AKT/mTOR中可靶向的下游突变缺失,药物中断尚未达到理想的效果。然而,PI3K/AKT/mTOR上游的膜相关基因突变在急性白血病中很常见,并且与PI3K/AKT/mTOR的异常激活有关,因此为进一步研究提供了良好的理论基础。本综述试图总结导致异常激活的关键发现,并反思靶向PI3K/AKT/mTOR治疗急性白血病的前景和挑战。我们的重点在于通过高通量数据采集获得的见解,为识别急性白血病的特定亚群作为PI3K/AKT/mTOR靶向治疗的理想候选者开辟了新的途径。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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