经选择的肺腺癌患者中EML4-ALK融合基因发生率的研究

目的探讨表皮生长因子受体(EGFR)野生型肺腺癌患者EML4-ALK融合基因的发生率是否高于EGFR状态未明者。方法经病理确诊的不吸烟或少吸烟的肺腺癌患者100例,EGFR野生型组50例,EGFR状态未明组50例,采用原位荧光杂交法(FISH)检测EML4-ALK融合基因状态。结果EGFR野生型组15例(30%)ML4-ALK融合基因阳性;EGFR状态未明组4例(8%)EML4-ALK融合基因阳性,2组差异有显著性(P<0.05);EML4-ALK融合基因发生率与年龄、性别、临床分期无明显相关性(P>0.05)。结论在不吸烟或少吸烟的肺腺癌患者中,经EGFR基因状态筛选可提高EML4-ALK融合基因检测阳性率。     

细胞蜡块、肺原发灶和转移灶组织在肺腺癌EGFR/ALK/ROS1基因联合检测中的应用

目的 探讨用457例肺腺癌患者的不同样本进行EAR(EGFR/ALK/ROS1)基因联合检测的意义。方法 纳入2020年1月至2022年8月经病理确诊为肺腺癌患者457例，分别对415例肺组织标本(131例活检标本和284例手术切除标本)、32例浆膜腔积液细胞蜡块、10例转移灶组织进行EAR基因联合检测，比较肺组织标本与细胞蜡块、转移灶组织EAR基因异常检出情况。结果 (1) 457例肺腺癌患者EAR突变总检出率为64.3%(294/457),EGFR/ALK/ROS1分别为56.2%(257/457)、4.8%(22/457)、3.3%(15/457);肺组织标本、细胞蜡块、转移灶组织EAR基因检出率分别为：62.7%(260/415)、84.4%(27/32)、70.0%(7/10),三者数据检出率存在着统计学差异(P<0.05),其中细胞蜡块与肺活检组织检出率相比，有统计学差异(P<0.017)。(2) 131例活检标本与284例手术切除标本EAR基因检出率分别为52.7%(69/131)、67.3%(191/284),手术切除标本比活检标本有更高的EAR基因检出率，...     

肺腺癌胸腔积液沉渣间变性淋巴瘤激酶融合基因蛋白表达与临床病理特征的关系及克唑替尼疗效观察

目的 探讨原发性肺腺癌胸腔积液沉渣间变性淋巴瘤激酶(ALK)蛋白表达与临床病理特征的关系及克唑替尼的治疗效果.方法 回顾性分析2013年9月至2014年1 1月首都医科大学附属北京胸科医院以胸腔积液沉渣包埋标本进行ALK基因重排检测的原发性肺腺癌病例85例,男42例,女43例,年龄30～87岁,平均58岁.采用Ventana全自动免疫组织化学染色和D5F3抗体试剂盒检测ALK蛋白表达,分析表达阳性患者的临床病理特征及克唑替尼的疗效.结果 85例标本中ALK蛋白表达阳性13例(15.3％);＜60岁患者ALK蛋白阳性12例,≥60岁1例(26.1％,2.6％,x2 =9.015,P=0.002);男性8例ALK蛋白表达阳性,女性5例(19.1％,11.6％,x2=0.903,P =0.259);不吸烟组ALK阳性8例,吸烟组5例(17.0％,13.5％,x2=0.379,P=0.827).13例ALK阳性患者中6例接受表皮生长因子受体(EGFR)基因突变检测,其中5例EGFR为野生型,1例不同肺叶病灶中检测出19外显子突变.13例ALK阳性患者中接受克唑替尼治疗4例,疗效评价均为部分缓解.结论 ALK蛋白阳性多见于晚期肺腺癌中较年轻的患者,ALK阳性患者罕见EGFR基因突变;对原发性肺腺癌合并胸膜转移出现恶性胸腔积液的患者,可根据胸腔积液沉渣包埋标本检测ALK蛋白表达,指导临床靶向治疗.     

表现为肺结节的早期肺腺癌病理与多种驱动基因关系探讨

目的探讨表现为肺结节的早期肺腺癌病理分期与驱动基因EGFR、ALK、ROS1、KRAS突变之间的关系。方法调取我院收治的40例手术切除表现为结节的早期肺腺癌与10例良性肺结节患者做对照,采用扩增阻滞突变系统(ARMS)法检测石蜡标本中该四种基因异常情况,分析驱动基因突变及病理分型的关系。结果 40例早期肺腺癌患者中31例检出突变,总突变率77.5%。四基因突变与结节组织分型密切相关(p0.05)。与原位腺癌及微浸润腺癌相比,浸润性肺腺癌具有更多的基因异常及更高的SUVmax及SUV代谢指数(P0.05),但四基因突变与SUVmax及SUV代谢指数均无明显相关性。结论早期肺腺癌即出现非常高的驱动基因异常,四基因异常达到77.5%。随着早期肺腺癌分期的发展,四基因异常检出率升高,提示以结节表现的肺腺癌早期发生、发展中,驱动基因异常发挥重要作用。     

中国人原发性肺腺癌EGFR基因突变分析

目的 探讨原发性肺腺癌表皮生长因子受体(EGFR)基因突变特点,及其与临床特征(性别、临床分期、吸烟情况)的关系.方法 采用PCR扩增和基因测序,检测133例原发性肺腺癌EGFR外显子18,19,20和21的突变情况,同时分析其突变与临床特征的关系.结果 133例中检测到EGFR基因突变50例(37.6%,50/133),EGFR 基因突变与性别和吸烟史相关,与临床分期无关.结论 使用EGFR酪氨酸激酶抑制剂治疗前进行EGFR基因检测非常必要.     

35岁以下肺癌患者基因突变状态及生存分析

目的 分析35岁以下肺癌患者基因突变状态与预后的关系.方法 对52例<35岁肺癌患者临床资料(年龄、性别、吸烟状态、初发临床表现、影像特点、疾病分期、治疗方案)、表皮生长因子受体(EGFR)突变、棘皮动物微管结合蛋白4-间变性淋巴瘤激酶(EML4-ALK)融合基因突变状态和生存状态进行回顾性分析.结果 52例患者中,女性较多(59.6%),腺癌最为常见(78.8%).47例为非小细胞肺癌,0~ⅢA期17例,ⅢB~Ⅳ30例,其中Ⅳ期27例.22例非小细胞肺癌患者行EGFR和EML4-ALK基因检测,7例(31.8%)EGFR突变阳性,6例(27.3%)EML4-ALK融合基因阳性.ALK阳性患者胸部CT影像表现为单发实质性肿块或结节的患者比例达83.3%,EGFR突变患者初诊即为Ⅳ期的比例达71.4%.50例随访患者的中位生存时间为24.6个月;分期早晚、手术与否、是否有基因突变是影响中位生存时间的主要因素.结论 年龄<35岁的肺癌患者以女性、腺癌、晚期居多;其EGFR、ALK基因突变检出率高于一般肺癌人群,ALK阳性患者胸部CT影像表现以单发实质性肿块或结节多见,EGFR突变患者初诊时大部分已达Ⅳ期;分期较早、行手术治疗、有基因突变等因素提示有较好预后.     

Survivin蛋白在肺腺癌中的表达及临床意义

目的探讨Survivin蛋白在肺腺癌组织中的表达及其与临床病理特征的关系。方法用链霉菌生物素蛋白-过氧化物酶免疫组织化学法(SP法),检测28例手术切除的肺腺癌组织、20例正常肺组织中Survivin蛋白的表达;并用末端转移酶标记(TUNEL)法检测凋亡指数(AI)。结果53.6%的肺腺癌组织有Survivin蛋白表达,20例正常肺组织中无Survivin蛋白表达(P<0.001)。Survivin蛋白与肺腺癌组织病理分级、TNM分期、淋巴结转移、预后、p53蛋白过表达呈正相关,而与性别、年龄、吸烟史无明显相关性(P均大于0.05)。AI显示出了Survivin蛋白的抗凋亡作用。结论Survivin蛋白在肺腺癌组织发生发展中起抑制癌细胞凋亡的重要作用,从而Survivin基因有望成为基因治疗的新靶点。     

不同病理类型肺癌组织中S100A6的表达情况及其临床意义

目的 探讨S100A6在不同病理类型肺癌组织中的表达情况及其临床意义。方法 回顾性选取2019年1月至2022年1月就诊于西安市人民医院的98例经病理学明确诊断的肺癌患者的肺癌组织标本，其中腺癌48例、鳞癌40例、小细胞肺癌（SCLC）8例、大细胞肺癌2例，同时选取8例肺癌患者的癌旁正常组织。收集患者的性别、年龄、有无吸烟史、病理类型、临床分期、分化程度、肿瘤直径、有无淋巴结转移、临床疗效。采用免疫组化检测S100A6表达情况。结果 不同性别、不同年龄、有无吸烟史、不同肿瘤直径、有无淋巴结转移、不同临床疗效的肺癌患者肺癌组织S100A6表达阳性率比较，差异无统计学意义（P>0.05）；不同病理类型、临床分期、分化程度的肺癌患者肺癌组织S100A6表达阳性率比较，差异有统计学意义（P<0.05）。不同性别、不同年龄、有无吸烟史、不同分化程度、不同肿瘤直径、有无淋巴结转移、不同临床疗效的腺癌及鳞癌患者肺癌组织S100A6表达阳性率比较，差异无统计学意义（P>0.05）；不同临床分期的腺癌及鳞癌患者肺癌组织S100A6表达阳性率比较，差异有统计学意义（P<0.05）。...     

MACC1、c-Met蛋白在肺癌中的表达及意义

目的 探讨肺鳞癌和肺腺癌癌组织中结肠癌转移相关基因(MACC)1和肝细胞生长因子受体(c-Met)的表达及其与临床病理学特征的关系。方法 应用免疫组化检测104例肺癌患者癌组织及癌旁正常肺组织中MACC1与c-Met蛋白的表达情况,分析两者与临床病理学参数的关系。结果 肺癌组织中MACC1阳性表达率[67.30%(70/104)]高于正常肺组织[23.08%(22/104)],差异有统计学意义(χ²=44.906,P<0.05)。肺癌组织中c-Met的阳性表达率[69.23%(72/104)]高于正常肺组织[23.08%(24/104)],差异有统计学意义(χ²=44.571,P<0.05)。肺鳞癌中c-Met的阳性表达率显著高于肺腺癌,吸烟组c-Met的阳性表达率显著高于非吸烟组(P<0.05)。MACC1与病理类型及吸烟史无关。MACC1及c-Met的表达水平与肺癌分化程度、TNM分期、淋巴结转移及术后生存时间均有明显关系;MACC1蛋白与c-Met蛋白表达呈正相关(P<0.05)。结论 MACC1与c-Met高表...     

非小细胞肺癌ROS1融合基因的靶向治疗研究进展

<正>ROS1融合基因是在2007年由科学家们[1,2]通过应用络氨酸激酶蛋白组学技术从一个肺腺癌患者肿瘤组织中筛选肿瘤致癌基因时与赖皮动物微管样蛋白4-间变淋巴瘤激酶(EML4-ALK)融合基因同时被发现的另一个融合基因。作为新的独特分子亚型代表,ROS1融合基因在非小细胞肺癌(NSCLC)中发生率约为1%~2%,远远低于EGFR基因突变率和ALK基因重排变异率(分别为10%~40%,3%     

Decoding Tumor Phenotypes for ALK,ROS1, and RET Fusions in Lung Adenocarcinoma Using a Radiomics Approach

Quantitative imaging using radiomics can capture distinct phenotypic differences between tumors and may have predictive power for certain phenotypes according to specific genetic mutations. We aimed to identify the clinicoradiologic predictors of tumors with ALK (anaplastic lymphoma kinase), ROS1 (c-ros oncogene 1), or RET (rearranged during transfection) fusions in patients with lung adenocarcinoma.A total of 539 pathologically confirmed lung adenocarcinomas were included in this retrospective study. The baseline clinicopathologic characteristics were retrieved from the patients’ medical records and the ALK/ROS1/RET fusion status was reviewed. Quantitative computed tomography (CT) and positron emission tomography imaging characteristics were evaluated using a radiomics approach. Significant features for the fusion-positive tumor prediction model were extracted from all of the clinicoradiologic features, and were used to calculate diagnostic performance for predicting 3 fusions’ positivity. The clinicoradiologic features were compared between ALK versus ROS1/RET fusion-positive tumors to identify the clinicoradiologic similarity between the 2 groups.The fusion-positive tumor prediction model was a combination of younger age, advanced tumor stage, solid tumor on CT, higher values for SUV_max and tumor mass, lower values for kurtosis and inverse variance on 3-voxel distance than those of fusion-negative tumors (sensitivity and specificity, 0.73 and 0.70, respectively). ALK fusion-positive tumors were significantly different in tumor stage, central location, SUV_max, homogeneity on 1-, 2-, and 3-voxel distances, and sum mean on 2-voxel distance compared with ROS1/RET fusion-positive tumors.ALK/ROS1/RET fusion-positive lung adenocarcinomas possess certain clinical and imaging features that enable good discrimination of fusion-positive from fusion-negative lung adenocarcinomas.     

非小细胞肺癌中EML4－ALK融合基因的检测及分析

目的检测非小细胞肺癌（NSCLC）患者中EML4-ALK基因的表达率并分析其与患者的临床病理学特征的关系。方法用荧光PCR法检测我院98例NSCLC患者肿瘤组织中EML4-ALK基因的表达。结果98例NSCLC患者中检测出6例有EML4-ALK基因的表达,表达率为6．12％。6例阳性患者中,4例为女性,2例为男性;不吸烟者4例,吸烟者2例;年龄〈50岁者5例,≥50岁者1例;5例为腺癌患者,1例为腺鳞癌患者;5例为中分化患者,1例为低分化患者,高分化患者中未发现阳性。结论EML4-ALK融合基因代表了NSCLC的-个新的分子亚型,表达EML4-ALK融合基因的NSCLC具有其独特的临床病理学特点。     

Identification of triple gene fusion ALK-LRRN2, LTBP1-ALK,and HIP1-ALK in advanced lung adenocarcinoma and response to alectinib: A case report

Rationale:Anaplastic lymphoma kinase (ALK) rearrangement is the second most common targetable oncogene-dirven gene in nonsmall cell lung cancer. Owing to the advanced sequencing technologies, new partner genes of ALK have been constantly detected.Patient concerns:A 42-year-old Chinese woman went to our hospital with the chief complaint of cough and expectoration for 1 month. The patient had no fever, chest pain, and hemoptysis.Diagnoses:She was diagnosed with advanced lung adenocarcinoma. The patient underwent lung biopsy guided by computed tomography and pathology showed poorly differentiated adenocarcinoma. To explore possibility of targeted therapy, the tumor samples were subjected to next-generation sequencing, and a rare 3 ALK fusion variant ALK-LRRN2, LTBP1-ALK, and HIP1-ALK was identified.Interventions and outcomes:The patient subsequently received alectinib treatment, and achieved partial response. No significant drug related adverse reactions were found during alectinib treatment. The progression-free survival achieved 25 months.Lessons:Together, we identified a rare triple ALK fusion variant, ALK-LRRN2, LTBP1-ALK and HIP1-ALK, in a patient with lung adenocarcinoma. The patient benefited from alectinib treatment, which could provide a certain reference for the patients with such gene alteration.     

Analysis of the molecular and clinicopathologic features of surgically resected lung adenocarcinoma in patients under 40 years old

Introduction

The youthful lung cancer may constitute an entity with distinct clinicopathologic characteristics and a controversial prognosis compared with the older counterpart. Whether the youthful lung cancer has the exclusively distinct molecular features has not been well investigated.

Methods

Thirty-six resected lung adenocarcinomas from young patients under 40 years old were analyzed concurrently for mutations in EGFR, KRAS, HER2, BRAF, AKT1, ALK, RET, TP53 and LKB1 and enrolled as the younger group. Their molecular and clinicopathologic characteristics were compared with those of 87 adenocarcinoma cases from patients above 40 years old which were collected as the older group.

Results

The comparable overall survival (OS) (P=0.942), more early adenocarcinomas (P=0.033), more wedge resections (P<0.001) and fewer smokers (P=0.004) were seen in the younger group, when compared with the clinicopathologic characteristics in the older group. Nineteen EGFR mutations (52.8%), 3 KRAS mutations (8.3%), 2 EML4-ALK fusions (5.6%) and 1 KIF5b-RET fusion (2.8%) were identified in the younger group. The difference of oncogenic mutations between the two groups was statistically insignificant (P=0.396). Twenty-six TP53 mutations (72.2%) and 4 LKB1 mutations (11.1%) were found in the younger group. When compared with the old patients, young patients showed a higher prevalence of TP53 mutations (P<0.001) and a comparable prevalence of LKB1 mutations (P=0.951).

Conclusions

The youthful lung cancer unequivocally presented the distinct clinicopathologic characteristics including more early adenocarcinomas and fewer smokers. It showed the similar oncogenic characteristics and higher prevalence of TP53 mutations compared with the older counterpart.     

Response to treatment with an ALK-TKI in a patient with advanced lung adenocarcinoma with concurrent ALK fusion and high PD-L1 expression: A case report

Rationale:Previous studies have shown that PD-L1 TPS ≥50% in lung cancer rarely overlaps with driver oncogenes such as epidermal growth factor receptor and anaplastic lymphoma kinase (ALK). The initial gene detection of the patient in this study showed ALK fusion combined with high expression of PD-L1. We explored the treatment options for this patient.Patient concerns:A 34-year-old woman presented for the first time with “repeated fever and cough for 20 days.” The patient denied any underlying medical history.Diagnosis:After a series of imaging examinations and needle biopsy, the patient was diagnosed as stage IV lung adenocarcinoma with multiple liver and bone metastases (EML4-ALK fusion, PD-L1 TPS 80%).Interventions:The patient was initially given alectinib targeted therapy. After progression, a second round of genetic testing was performed and the patient was detected to have both ALK fusion and BRAF mutation. The patient was then successively changed to treatment with ensatinib combined with dabrafenib, and lorlatinib combined with dabrafenib.Outcomes:The initial efficacy evaluation of alectinib was PR, but its PFS was only 4 months. The patient only achieved an overall survival of 10 months.Lessons:Non–small cell lung cancer with an ALK fusion and high PD-L1 expression responds poorly to most current treatment options, with survival time after ALK-tyrosine kinase inhibitor treatment notably shorter than that of patients with an ALK fusion alone.     

中性粒细胞—淋巴细胞比率与肺癌临床病理特征的关系

目的 探讨中性粒细胞—淋巴细胞比率（NLR）与肺癌临床病理特征的关系.方法 收集行手术治疗的234例肺癌患者的一般信息、术前中性粒细胞计数、淋巴细胞计数、手术方式及术后病理等临床病理特征资料,分析NLR（血常规中性粒细胞计数/淋巴细胞计数）与肺癌临床病理特征的关系.结果 男性、有吸烟史、病理分期晚、分化程度低的患者NLR较高;高NLR者中男性患者、吸烟患者比例更高,肿瘤最大径较大,肿瘤分期晚.结论 NLR与肺癌患者性别、吸烟史、分期及分化程度相关,NLR增高提示肿瘤分期偏晚、肿瘤较大.NLR可作为肺癌患者的常规检查项目,可为判断患者预后提供依据.     

Profile of entrectinib in the treatment of ROS1-positive non-small cell lung cancer: Evidence to date

ROS proto-oncogene 1 (ROS1) encodes a type I integral membrane protein with tyrosine kinase activity and whose activating alterations are involved in the aggressiveness of several tumor types. Fusions involving ROS1 gene are present in 1–2% of lung adenocarcinomas and other solid tumors. Entrectinib, also known as RXDX-101, is a potent second-generation, multitarget oral inhibitor against NTRK1, NTRK2, NTRK3, ALK, and ROS1 with the ability to cross the blood–brain barrier. Results of Phase I and II trials have led the Food and Drug Administration to grant approval to entrectinib for the treatment of patients with metastatic, ROS1-positive non-small cell lung cancer (NSCLC). In this review, we will describe the biology of ROS1, as well as results of the efficacy and safety of different clinical trials evaluating entrectinib in ROS1-positive NSCLC.     

Structural insight into selectivity and resistance profiles of ROS1 tyrosine kinase inhibitors

Oncogenic ROS1 fusion proteins are molecular drivers in multiple malignancies, including a subset of non-small cell lung cancer (NSCLC). The phylogenetic proximity of the ROS1 and anaplastic lymphoma kinase (ALK) catalytic domains led to the clinical repurposing of the Food and Drug Administration (FDA)-approved ALK inhibitor crizotinib as a ROS1 inhibitor. Despite the antitumor activity of crizotinib observed in both ROS1- and ALK-rearranged NSCLC patients, resistance due to acquisition of ROS1 or ALK kinase domain mutations has been observed clinically, spurring the development of second-generation inhibitors. Here, we profile the sensitivity and selectivity of seven ROS1 and/or ALK inhibitors at various levels of clinical development. In contrast to crizotinib’s dual ROS1/ALK activity, cabozantinib (XL-184) and its structural analog foretinib (XL-880) demonstrate a striking selectivity for ROS1 over ALK. Molecular dynamics simulation studies reveal structural features that distinguish the ROS1 and ALK kinase domains and contribute to differences in binding site and kinase selectivity of the inhibitors tested. Cell-based resistance profiling studies demonstrate that the ROS1-selective inhibitors retain efficacy against the recently reported CD74-ROS1^G2032R mutant whereas the dual ROS1/ALK inhibitors are ineffective. Taken together, inhibitor profiling and stringent characterization of the structure–function differences between the ROS1 and ALK kinase domains will facilitate future rational drug design for ROS1- and ALK-driven NSCLC and other malignancies.Constitutively activated kinase fusion proteins that arise from somatic chromosomal rearrangements are frequent drivers of malignant transformation in cancer and represent a targetable vulnerability for clinical intervention. The clinical success of the tyrosine kinase inhibitor (TKI) imatinib in targeting the oncogenic BCR-ABL1 fusion protein in chronic myeloid leukemia (CML) motivated efforts to identify and target oncogenic kinases in other cancers (1–3). One such setting is non-small cell lung cancer (NSCLC), where chromosomal rearrangements of the receptor tyrosine kinase (RTK) anaplastic lymphoma kinase (ALK) are found in 4–5% of patients (4, 5). The validation of rearranged ALK as an oncogenic driver prompted the discovery and clinical implementation of crizotinib as the first clinical targeted inhibitor for use in ALK fusion-positive NSCLC (6, 7).Fusion proteins involving the highly related kinase ROS1, an orphan RTK of the insulin receptor family, are present in ∼1% of NSCLC patients. ROS1 rearrangements span a variety of fusion partners across several other epithelial malignancies, including cholangiocarcinoma, gastric cancer, and ovarian cancer (4, 8). CD74-ROS1 is the most frequent ROS1 fusion detected in NSCLC. ROS1 fusion proteins are transforming drivers that contribute to tumorigenesis or tumor progression in multiple experimental model systems (9–11).Approximately 75,000 and 15,000 new NSCLC patients per year are anticipated to harbor tumors driven by rearranged ALK or ROS1, respectively. Although mutually exclusive in a given tumor and considered to be distinct molecular subgroups (12), patients presenting with ROS1 or ALK fusion-driven lung cancer share clinical features, tend to be younger compared with other NSCLC patients, and have little to no history of smoking. The kinase domains of ROS1 and ALK display a high degree of sequence homology (13), prompting investigation of crizotinib for activity against ROS1 (12). Recent phase I data confirmed significant responses to crizotinib in ROS1-rearranged NSCLC patients (14, 15).Despite the demonstrated clinical efficacy of TKI-based targeted therapies in cancer, a universal challenge is emergence of drug resistance and ensuing disease progression. Resistance commonly involves either acquisition of kinase domain mutations that compromise inhibitor binding or activation of alternative pathways that provide compensatory cell survival signals. Concordant with previous clinical experience from other TKIs, such as imatinib in CML and erlotinib or gefitinib in lung cancer (16–18), resistance due to acquisition of kinase domain mutations is frequently observed in crizotinib-treated NSCLC patients harboring ALK fusions (7, 19–21). This experience has prompted the development of several second-generation ALK inhibitors capable of circumventing resistance. Furthermore, compared with ALK-rearranged lung cancers, ROS1-rearranged cancers are less frequent, and clinical benefit with crizotinib may be more durable. The median progression-free survival for crizotinib-treated patients from phase I evaluation of ROS1-rearranged NSCLC is 19.2 mo (15), compared with 7.7 mo for patients with ALK-rearranged disease (phase III data) (14). Given these factors, mechanisms of acquired resistance to crizotinib in the clinic may take longer to identify, and only the CD74-ROS1^G2032R mutation has been reported to date (22).We have previously reported that foretinib (XL-880) is a potent ROS1 inhibitor that retains efficacy against the crizotinib-resistant CD74-ROS1^G2032R mutant in cell-based assays (23). In contrast to crizotinib’s dual ROS1/ALK efficacy, we observed that foretinib is a poor ALK inhibitor. These findings establish that not all ROS1 inhibitors possess inhibitory reciprocity for ALK, and drug discovery efforts that use one kinase as a proxy for the other may face limitations.Here, we report in vitro profiling of a panel of clinically relevant ROS1 and ALK inhibitors. To complement cell-based resistance profiling of ROS1-selective inhibitors, structural comparison of the kinase domains of ROS1 and ALK and computational modeling of TKI binding to native and mutant kinase domains were also performed. These results provide insights into therapeutically exploitable structural differences between ROS1 and ALK that impact inhibitor binding and design.     

Clinical features and mutation status of EGFR,KRAS, BRAF,EML4-ALK and ROS1 between surgical resection samples and non surgical resection samples in lung cancer

Background

Target therapy is the first-line treatment in lung cancer. The testing of driver gene mutations is crucial for decision of treatment. Many lung cancer patients are in advanced grade, and lose the chance of operation.

Methods

The tissue used to perform mutation testing is only from biopsy. In order to analysis the difference between surgical resection samples (SRSs) and non-surgical resection samples (NSRSs), 1,357 surgical tissues and 145 biopsy samples histopathologically diagnosed with lung cancer were collected to detect the mutation status of EGFR, KRAS, BRAF, EML4-ALK and ROS1 in this study.

Results

There were no significant differences of age, gender, and histological type between the two group patients we collected; however, the significant difference was present in grade. More early stage patients were in the surgical group, but more advanced stage lung cancer patients were in non surgical group. In the mutation analysis, we also found no significant differences in all driver genes we detected between the two groups.

Conclusions

Both surgical resection samples and biopsy samples could be used to perform the testing the driver gene mutation.     

抑癌基因P16在肺鳞癌和肺腺癌中的表达及临床意义

目的 探讨p16基因产物在肺鳞癌和肺腺癌中的表达及其意义。方法 本组56例原发性非小细胞肺癌，其中鳞癌37例，腺癌19例。用免疫组织化学PCR法检测患者肺癌新鲜标本p16蛋白表达水平。结果 56例肺癌标本中p16蛋白阳性表达率为58.9%（33／56），伴有淋巴结转移者其阳性表达率41.4%（12／29）显著低于无淋巴结转移者（P16阳性表达率为77.8%（21／27），P＜0.01）。P16蛋白阴性表达者的1年、3年生存率分别为59.7%、44.1%，显著低于p16蛋白阳性表达者85.2%、71.8%。结论 p16蛋白表达与肺鳞癌和肺腺癌的组织类型，淋巴结转移及预后有关。p16蛋白状态可作为判断肺癌预后的指标之一。