Adaptive stress signaling in targeted cancer therapy resistance.
Adaptive stress signaling in targeted cancer therapy resistance.
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DOI：
10.1038/onc.2015.26
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发表时间：
2015-11-05
期刊：
影响因子：
8
通讯作者：
Bivona TG
中科院分区：
文献类型：
--
作者：
Pazarentzos E;Bivona TG
识别驱动癌症发生和发展的特定遗传改变以及开发针对这些驱动改变的靶向药物，已经彻底改变了许多人类癌症的治疗。虽然使用这种靶向癌症疗法已经取得了实质性进展，但耐药性仍然是限制整体临床影响的主要挑战。因此，尽管取得了进展，但仍需要新的策略来增强对靶向癌症治疗的反应并消除对靶向癌症治疗的耐药性，以便在患者中实现持久或治愈性反应。迄今为止，表征耐药机制的努力主要集中在介导患者原发性或继发性耐药的分子事件上。对肿瘤细胞暴露于靶向药物后早期可能发生的初始分子反应和适应知之甚少。虽然研究不足，但新出现的证据表明，肿瘤细胞对靶向治疗压力的早期适应性变化可能对治疗期间肿瘤细胞的存活和耐药性的发展至关重要。在这里，我们回顾了最近的数据，阐明了肿瘤细胞中适应性应激信号转导的分子结构。我们强调如何利用这些知识可以催化新的策略，以最大限度地减少或消除靶向治疗耐药性，从而释放靶向治疗的全部潜力，将许多癌症从致命性转变为慢性或可治愈的疾病。
The identification of specific genetic alterations that drive the initiation and progression of cancer and the development of targeted drugs that act against these driver alterations has revolutionized the treatment of many human cancers. While substantial progress has been achieved with the use of such targeted cancer therapies, resistance remains a major challenge that limits the overall clinical impact. Hence, despite progress, new strategies are needed to enhance response and eliminate resistance to targeted cancer therapies in order to achieve durable or curative responses in patients. To date, efforts to characterize mechanisms of resistance have primarily focused on molecular events that mediate primary or secondary resistance in patients. Less is known about the initial molecular response and adaptation that may occur in tumor cells early upon exposure to a targeted agent. Although understudied, emerging evidence indicates that the early adaptive changes by which tumor cells respond to the stress of a targeted therapy may be crucial for tumor cell survival during treatment and the development of resistance. Here, we review recent data illuminating the molecular architecture underlying adaptive stress signaling in tumor cells. We highlight how leveraging this knowledge could catalyze novel strategies to minimize or eliminate targeted therapy resistance, thereby unleashing the full potential of targeted therapies to transform many cancers from lethal to chronic or curable conditions.