Advances in Molecular Biology of Lung Disease Aiming for Precision Therapy in Non-small Cell Lung Cancer
Advances in Molecular Biology of Lung Disease Aiming for Precision Therapy in Non-small Cell Lung Cancer
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DOI：
10.1378/chest.14-2663
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发表时间：
2015-10-01
期刊：
影响因子：
9.6
通讯作者：
Sethi, Tariq
中科院分区：
文献类型：
--
作者：
Rooney, Claire;Sethi, Tariq
肺癌是发达国家癌症相关死亡的主要原因，占所有癌症死亡人数的近四分之一。传统的治疗算法在很大程度上依赖于组织学亚型，并包含了疗效有限的实用化疗方案。然而，由于我们对非小细胞肺癌(NSCLC)疾病的分子基础的了解已经成倍地提高，很明显，NSCLC可以根据特定癌基因中反复发生的驱动因素突变来从根本上细分，或从分子上表征。我们知道，这种突变的存在导致异常信号蛋白的结构性激活，这些异常信号蛋白启动、发展和维持肿瘤的发生。这种持续的恶性表型被称为“癌基因成瘾”。在此基础上，治疗方法发生了范式转变。理性的、有针对性的疗法已经被开发出来，第一个是酪氨酸激酶抑制剂(TKIs)，它在10年前进入了临床领域。这些治疗非常成功，显著影响了非小细胞肺癌的自然病程，并改善了患者的预后。然而，这些药物的益处在某种程度上受到适应性耐药机制的出现的限制，解决这一现象的努力正在进行中。更好地了解所有类型的癌基因驱动的非小细胞肺癌和TKI耐药的发生将有助于我们进一步开发第二代和第三代小分子抑制剂，并将扩大我们对这种疾病的精确治疗范围。
Lung cancer is the principal cause of cancer-related mortality in the developed world, accounting for almost one-quarter of all cancer deaths. Traditional treatment algorithms have largely relied on histologic subtype and have comprised pragmatic chemotherapy regimens with limited efficacy. However, because our understanding of the molecular basis of disease in non-small cell lung cancer (NSCLC) has improved exponentially, it has become apparent that NSCLC can be radically subdivided, or molecularly characterized, based on recurrent driver mutations occurring in specific oncogenes. We know that the presence of such mutations leads to constitutive activation of aberrant signaling proteins that initiate, progress, and sustain tumorigenesis. This persistence of the malignant phenotype is referred to as "oncogene addiction." On this basis, a paradigm shift in treatment approach has occurred. Rational, targeted therapies have been developed, the first being tyrosine kinase inhibitors (TKIs), which entered the clinical arena > 10 years ago. These were tremendously successful, significantly affecting the natural history of NSCLC and improving patient outcomes. However, the benefits of these drugs are somewhat limited by the emergence of adaptive resistance mechanisms, and efforts to tackle this phenomenon are ongoing. A better understanding of all types of oncogene-driven NSCLC and the occurrence of TKI resistance will help us to further develop second- and third-generation small molecule inhibitors and will expand our range of precision therapies for this disease.