PAK Group I的活性减弱促进肺癌细胞对EGFR-TKIs的敏感性

目的:探讨p21活化激酶(p21-activated kinase,PAK)是否影响肺癌细胞对EGFR-TKIs的敏感性.方法:肺癌细胞系中加入PAK Group I抑制剂(IPA3)后,应用MTT、流式细胞术观察肺癌细胞的增殖能力.结果:IPA3和吉非替尼虽然能在不同程度上抑制肺癌细胞的增殖,但二者的联合用药能明显增强对肺癌细胞增殖的抑制作用.结论:PAK Group I的活性减弱后能抑制肺癌细胞的增殖,促进肺癌细胞对EGFR-TKIs的敏感性.     

miRNA-200a调控FOXC1增敏肺癌EGFR-TKI治疗的研究

目的：探究miRNA-200a对非小细胞肺癌（non-small cell lung cancer, NSCLC）靶向治疗疗效的影响及其调控机制。方法：通过RT-PCR、Western blot等方法检测NSCLC细胞中miRNA-200a、FOXC1的表达量;四甲基偶氮唑盐（MTT）实验、细胞划痕实验、Transwell实验分别检测miRNA-200a、FOXC1对肺腺癌细胞生长、迁移、侵袭等生物学行为的影响;荧光素酶报告实验分析FOXC1与miRNA-200a的靶向关系。结果：高表达miRNA-200a抑制肺腺癌细胞的生长、上皮间质转化、迁移、侵袭,并且增加肺腺癌细胞对吉非替尼的敏感性。此外,敲低FOXC1同样可以抑制细胞生长,恢复肺腺癌细胞对吉非替尼敏感性。结论：上调miRNA-200a或下调FOXC1可以增强NSCLC细胞对吉非替尼的敏感性。为克服表皮生长因子受体酪氨酸激酶抑制剂治疗的耐药性提供了一种新的有效治疗方法。     

Redundant kinase activation and resistance of EGFR-tyrosine kinase inhibitors

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have shown dramatic effects against that tumors harboring EGFR activating mutations in the EGFR intracytoplasmic tyrosine kinase domain and resulted in cell apoptosis. Unfortunately, a number of patients ultimately developed resistance by multiple mechanisms. Thus, elucidation of the mechanism of resistance to EGFR-TKIs can provide strategies for blocking or reversing the situation. Recent studies suggested that redundant kinase activation plays pivotal roles in escaping from the effects of EGFR-TKIs. Herein, we aimed to characterize several molecular events involved in the resistance to EGFR-TKIs mediated by redundant kinase activation.     

凡德他尼治疗5例晚期复治肺腺癌患者的临床观察及相关文献回顾

背景与目的凡德他尼是一种多靶点口服的小分子抑制剂,可同时作用于血管内皮生长因子受体、表皮生长因子受体、RET酪氨酸激酶转染中的重排,本研究旨在探讨凡德他尼治疗晚期复治肺腺癌患者的疗效和副反应。方法患者经过化疗和特罗凯治疗失败后,给予凡德他尼300 mg每日1次口服。结果 5例患者中,2例(40%)最佳疗效达疾病稳定(stable disease,SD),3例(60%)疗效均为疾病进展(progressive disease,PD)。随访40个月,1例患者目前仍在随访中。中位无疾病进展时间(progression free survival,PFS)为2个月,平均总生存期(overall survival,OS)为22.6个月。出现副反应包括皮疹(n=2)、皮肤改变(n=2)、甲沟炎(n=2)、无症状的心电图QTc延长(n=2)、ST-T改变(n=1)、腹泻(n=1)、转氨酶增高(n=1)。结论凡德他尼治疗晚期复治肺腺癌患者中位PFS为2个月,平均OS为22.6个月,具有较好的安全性,结果同相关文献报道类似。     

吉非替尼靶向治疗中晚期非小细胞肺癌40例

目的:观察吉非替尼在中晚期非小细胞肺癌的疗效。方法:40例晚期非小细胞肺癌患者口服吉非替尼250mg/d,观察RR、DCR、PFS、OS及不良反应发生率。结果:40例患者中,CR 1例,PR 18例,SD 13例,PD 8例,RR为47.5%,吉非替尼在优势人群中有效率约72%左右;中位有效时间为8~10个月。结论:吉非替尼在EGFR基因突变患者中疗效明显,可显著延长生存期,提高生活质量,且安全性高,毒性可耐受。在女性、腺癌、不吸烟人群中疗效更明确,临床获益显著。     

miR-340 与Nrf2 在非小细胞肺癌患者靶向治疗耐药中的表达及相关性分析

目的探究miR-340与Nrf2在非小细胞肺癌患者靶向治疗耐药中的表达及意义。方法选取2016年1月—2019年12月我院收治的EGFR基因突变非小细胞肺癌表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)耐药患者42例作为观察组,同期于我院治疗的非耐药患者42例为对照组,检测并比较两组患者miR-340、Nrf2表达水平,同时探究miR-340水平与Nrf2的相关性。结果观察组患者血清miR-340水平显著高于对照组(P<0.05),Nrf2水平显著低于对照组(P<0.05);miR-340与Nrf2水平呈负相关(P<0.05);进一步Logistic分析显示,miR-340表达上调及Nrf2表达下调是非小细胞肺癌患者EGFR-TKIs耐药发生的独立危险因素。结论miR-340可通过影响体内Nrf2水平参与EGFR-TKIs耐药的发生,为提高肺腺癌的诊治提供了新的理论依据及潜在干预靶点。     

Long non-coding RNA UCA1 induces non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway in EGFR-mutant non-small cell lung cancer

The aim of this study was to explore the role of long non-coding RNA UCA1 (urothelial cancer-associated 1) in acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in EGFR-mutant non-small cell lung cancer (NSCLC). In our study, UCA1 expression was significantly increased in lung cancer cells and patients with acquired resistance to EGFR-TKIs. Over-expression of UCA1 was significantly associated with a shorter progression-free survival (PFS) [13.0 vs. 8.5 months, P < 0.01] in tumors with respond to EGFR-TKIs. The significant relationship was not observed in patients with T790M mutation (10.5 vs. 12.0 months, P = 0.778), but in patients with non-T790M (19.0 vs. 9.0 months, P = 0.023). UCA1 knockdown restored gefitinib sensitivity in acquired resistant cells with non-T790M and inhibited the activation of the AKT/mTOR pathway and epithelial-mesenchymal transition (EMT). The mTOR inhibitor was effective in UCA1-expressing cell PC9/R. Inhibiting mTOR could change the expression of UCA1, although there was no significant difference. In conclusion, the influence of over-expression of UCA1 on PFS for patients with acquired resistance to EGFR-TKIs was from the subgroup with non-T790M mutation. UCA1 may induce non-T790M acquired resistance to EGFR-TKIs by activating the AKT/mTOR pathway and EMT.     

EGFR-TKIs辅助治疗非小细胞肺癌的临床观察

目的：探讨非小细胞肺癌患者EGFR-TKIs辅助治疗的临床疗效及安全性。方法选取127例非小细胞肺癌患者,给予EGFR-TKIs辅助化疗4周后,依据RECIST 1．1标准评价短期临床治疗效果,疾病控制较好患者继续进行EGFR-TKIs辅助化疗,并依据RECIST 1．1标准评价长期临床治疗效果;WHO标准评价不良反应;Kaplan-Meier方法分析EGFR-TKIs辅助治疗非小细胞肺癌后2年生存率。结果 EGFR-TKIs辅助治疗非小细胞肺癌4周后32．28％患者达到病理部分缓解,51．97％患者病情稳定,治疗有效率为32．28％,疾病控制率为84．25％;EGFR-TKIs辅助治疗非小细胞肺癌长期治疗后40．94％患者达到病理部分缓解,14．96％患者病情稳定,治疗有效率为40．94％,疾病控制率为55．91％。皮疹、转氨酶升高、腹泻、胃肠道刺激等是EGFR-TKIs辅助治疗非小细胞肺癌的不良反应,患者Ⅲ～Ⅳ级不良反应发生率较低（主要是皮疹）;患者2年总回访率为96．06％,中位无进展生存期5．3个月,辅助化疗后2年生存率为2．36％。结论 EGFR基因突变型非小细胞肺癌患者接受EGFR-TKIs辅助化疗,临床治疗效果较好且患者耐受性较好。但是治疗后期EGFR-TKIs耐药是影响非小细胞肺癌患者生存率的重要因素。     

Pharmacokinetics of edoxaban in EGFR-mutated non-small cell lung cancer patients with venous thromboembolism

BackgroundThe risk of venous thromboembolism (VTE) is increased 7-fold in patients with cancer than in those without. Low-molecular-weight heparin is the standard treatment for cancer-associated VTE. Direct oral anticoagulants (DOACs) are not inferior to low-molecular-weight heparin with respect to the general outcome of recurrent VTE. Warfarin is associated with a risk of bleeding when used in combination with gefitinib or erlotinib which are epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs). It is unclear, however, whether combination treatments with EGFR-TKIs and DOACs pose the same risk. We aimed to identify anticancer drugs and anticoagulants that can be used safely in combination, as accompanying research to an observational study on VTE incidence rates in lung cancer patients (Rising-VTE/NEJ037 study).MethodsTwelve patients receiving EFGR-TKI monotherapy and VTE treatment were enrolled. Blood samples were collected in time series after the first dose of edoxaban, and further samples were collected within 8–15 days after administering EGFR-TKIs. The pharmacokinetics (PK) of edoxaban were analyzed using a non-compartmental model.ResultsEdoxaban concentrations (30 mg once daily) were measured in eight patients. PK analyses showed no significant differences before and after co-administration of EGFR-TKIs (gefitinib, erlotinib, and afatinib).ConclusionsOur findings indicate that the PK of edoxaban was not considerably affected by co-administration of EGFR-TKIs (gefitinib, erlotinib, and afatinib).