IHC、FISH和RT-PCR检测对EML4-ALK重排的一致性

棘皮动物微管结合蛋白-间变性淋巴瘤激酶（echinoderm microtubule-associated prote i n-l ike4-anaplastic lymphoma kinase,EML4-ALK）在肺癌中已成为第二个最重要的驱动致癌基因,在4%-6%的肺腺癌中EML4-ALK已经成为第一个可以靶向治疗的融合基因位点。伴随着ALK分离探针荧光原位杂交（fluorescent in situ hybridization,FISH）试剂盒的上市,克唑替尼已经被批准治疗ALK阳性的进展期非小细胞肺癌（non-small cell lung cancer,NSCLC）。然而,一种靶向药物的成功主要取决于一种敏感且特异的筛选实验方法来检测分子药物作用的靶点。以作者的经验看,用RTPCR来检测EML4-ALK,比用FISH和免疫组化（immunohistochemistry,IHC）方法更敏感,结果更可靠。尽管通过FISH检测ALK已经经过大量的临床实验验证,然而该方法在技术层面仍存在许多具有挑战性的问题,而通过IHC和RT-PCR方法检测ALK仍需要临床进一步的探索。

Assays for predicting and monitoring responses to lung cancer immunotherapy

Immunotherapy has become a key strategy for cancer treatment, and two immune checkpoints, namely, programmed cell death 1(PD-1) and its ligand(PD-L1), have recently emerged as important targets. The interaction blockade of PD-1 and PD-L1 demonstrated promising activity and antitumor efficacy in early phase clinical trials for advanced solid tumors such as non-small cell lung cancer(NSCLC). Many cell types in multiple tissues express PD-L1 as well as several tumor types, thereby suggesting that the ligand may play important roles in inhibiting immune responses throughout the body. Therefore, PD-L1 is a critical immunomodulating component within the lung microenvironment, but the correlation between PD-L1 expression and prognosis is controversial. More evidence is required to support the use of PD-L1 as a potential predictive biomarker. Clinical trials have measured PD-L1 in tumor tissues by immunohistochemistry(IHC) with different antibodies, but the assessment of PD-L1 is not yet standardized. Some commercial antibodies lack specificity and their reproducibility has not been fully evaluated. Further studies are required to clarify the optimal IHC assay as well as to predict and monitor the immune responses of the PD-1/PD-L1 pathway.

Advances in immunotherapy for treatment of lung cancer

Different approaches for treating lung cancer have been developed over time, including chemotherapy, radiotherapy and targeted therapies against activating mutations. Lately, better understanding of the role of the immunological system in tumor control has opened multiple doors to implement different strategies to enhance immune response against cancer cells. It is known that tumor cells elude immune response by several mechanisms. The development of monoclonal antibodies against the checkpoint inhibitor programmed cell death protein 1(PD-1) and its ligand(PD-L1), on T cells, has led to high activity in cancer patients with long lasting responses. Nivolumab, an anti PD-1 inhibitor, has been recently approved for the treatment of squamous cell lung cancer patients, given the survival advantage demonstrated in a phase III trial. Pembrolizumab, another anti PD-1 antibody, has received FDA breakthrough therapy designation for treatment of non-small cell lung cancer(NSCLC), supported by data from a phase I trial. Clinical trials with anti PD-1/PD-L1 antibodies in NSCLC have demonstrated very good tolerability and activity, with response rates around 20% and a median duration of response of 18 months.

Understanding the function and dysfunction of the immune system in lung cancer: the role of immune checkpoints

Survival rates for metastatic lung cancer, including non-small cell lung cancer(NSCLC) and small cell lung cancer(SCLC), are poor with 5-year survivals of less than 5%. The immune system has an intricate and complex relationship with tumorigenesis; a groundswell of research on the immune system is leading to greater understanding of how cancer progresses and presenting new ways to halt disease progress. Due to the extraordinary power of the immune system—with its capacity for memory, exquisite specificity and central and universal role in human biology—immunotherapy has the potential to achieve complete, long-lasting remissions and cures, with few side effects for any cancer patient, regardless of cancer type. As a result, a range of cancer therapies are under development that work by turning our own immune cells against tumors. However deeper understanding of the complexity of immunomodulation by tumors is key to the development of effective immunotherapies, especially in lung cancer.

PD-L1 expression associated with better response to EGFR tyrosine kinase inhibitors

Cancer evades host immune surveillance by using immune checkpoints,w hich are inhibitor y pathways cr ucial for maintaining self-tolerance1.Tumor cells express multiple inhibitory ligands,and tumor-infiltrating lymphocytes(TIL)express a variety of inhibitory receptors.Inhibitory receptors cytotoxic T-lymphocyte-associated protein 4(CTLA-4)and programmed

ALK和ROS1:肺癌治疗的联合靶点

间变性淋巴瘤激酶(anaplastic lymphoma kinase,ALK)基因重排可见于包括非小细胞肺癌(non small cell lung cancer,NSCLC)在内的多种恶性肿瘤中。ALK融合基因使激酶具有异常活性,而野生型ALK激酶域突变也可使它被激活。ALK基因重排使得NSCLC中出现了新的分子亚型,该亚型对ALK抑制剂高度耐药。克唑替尼(crizotinib)是一个口服小分子ATP模拟化合物,它最初作为MET抑制剂被开发,随后被发现具有抗ALK活性的脱靶效应(off target),并被美国FDA批准用于治疗ALK阳性的NSCLC患者。近来在NSCLC患者中还发现了ROS1受体酪氨酸激酶染色体重排,而克唑替尼正处于治疗该分子亚型NSCLC患者的临床试验中。任何计算机辅助药物设计都是依赖其分子结构和配体的药物设计方法,每种方法的详细信息中均应重点强调利用这二者,以开发多靶点小分子激酶抑制剂。此类多靶点小分子激酶抑制剂均可对ROS1和ALK重排的NSCLC有抑制增殖作用。因此,本综述重点强调了关于靶向这些激酶的重要性,以及在优化出效能更佳、选择性更强的ROS1和ALK激酶抑制剂中所取得的进步。