Signaling Intermediates (MAPK and PI3K) as Therapeutic Targets in NSCLC
Signaling Intermediates (MAPK and PI3K) as Therapeutic Targets in NSCLC
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DOI：
10.2174/13816128113196660763
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发表时间：
2014-01-01
影响因子：
3.1
通讯作者：
Milella, Michele
中科院分区：
文献类型：
--
作者：
Ciuffreda, Ludovica;Incani, Ursula Cesta;Milella, Michele
RAS/RAF/MEK/ERK和PI 3 K/AKT/mTOR途径控制基本的生理过程，例如细胞增殖、分化、代谢、细胞骨架重组和细胞死亡和存活。这些信号转导通路的组成性激活是癌症的必要标志，并且这些通路的遗传或表观遗传基础上的失调已经涉及肺癌的起始、进展和恶性扩散。因此，靶向MAPK和PI 3 K级联的组分是开发治疗肺癌的新治疗方法的有吸引力的策略，尽管迄今为止使用单一途径抑制剂的临床成功有限。事实上，已经证明存在通路内和通路间补偿环，其在药理学阻断点的上游或下游重新激活非常相同的级联，或在阻断一种信号传导级联后激活替代通路，可能驱动临床前（和可能的临床）耐药性。因此，与单一药剂相比，用信号传导抑制剂的组合阻断两种途径可能导致更有效的抗肿瘤作用，并且因此潜在地克服和/或延迟临床抗性。本文综述了NSCLC中MAPK和PI 3 K级联反应之间通路串扰的临床前和临床研究现状以及联合靶向治疗通路的基本原理。
The RAS/RAF/MEK/ERK and the PI3K/AKT/mTOR pathways govern fundamental physiological processes, such as cell proliferation, differentiation, metabolism, cytoskeleton reorganization and cell death and survival. Constitutive activation of these signal transduction pathways is a required hallmark of cancer and dysregulation, on either genetic or epigenetic grounds, of these pathways has been implicated in the initiation, progression and metastastic spread of lung cances. Targeting components of the MAPK and PI3K cascades is thus an attractive strategy in the development of novel therapeutic approaches to treat lung cancer, although the use of single pathway inhibitors has met with limited clinical success so far. Indeed, the presence of intra-and inter-pathway compensatory loops that re-activate the very same cascade, either upstream or downstream the point of pharmacological blockade, or activate the alternate pathway following the blockade of one signaling cascade has been demonstrated, potentially driving preclinical (and possibly clinical) resistance. Therefore, the blockade of both pathways with combinations of signaling inhibitors might result in a more efficient anti-tumor effect, and thus potentially overcome and/or delay clinical resistance, as compared with single agent. The current review aims at summarizing the current status of preclinical and clinical research with regard to pathway crosstalks between the MAPK and PI3K cascades in NSCLC and the rationale for combined therapeutic pathway targeting.