Tyrosine kinase inhibitors and human epidermal growth factor receptor-2 positive breast cancer

The body of evidence investigating human epidermal growth factor receptor-2(HER2)directed therapy in patients with breast cancer(BC)has been growing within the last decade.Recently,the use of tyrosine kinase inhibitors(TKIs)has been of particular interest in the treatment of human malignancies.This literature commentary is intended to highlight the most recent findings associated with the widely-studied TKI agents and their clinical significance in improving the outcomes of HER2 positive BC.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer(NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858 R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Secondgeneration EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.

Therapeutic Effect of First-line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI)Combined with Whole Brain Radiotherapy on Patients with EGFR Mutation-positive Lung Adenocarcinoma and Brain Metastases

This study compared the therapeutic effect of first-line epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)with that of EGFR-TKI plus whole brain radiotherapy(WBRT)on patients with EGFR mutation-positive lung adenocarcinoma and brain metastases.A total of 139 patients with lung adenocarcinoma and brain metastases treated with first-line EGFR-TK1therapy from September 2008 to December 2017 were enrolled in this study.The study endpoints were intracranial time to progression(TTP)and overall survival(OS).The effects of clinical pathological parameters and EGFR gene status on the study endpoints were compared.The results showed that the intracranial TTP was significantly longer in EGFR-TKI plus WBRT group than in EGFR-TKI group (median 30.0 vs.18.2 months,χ2=10.824,P=0.001),but no significant difference in the OS was noted between the two groups (median 48.0 vs.41.1 months,χ2=0.012, P=0.912).Also,there was no statistically significant difference in the OS between patients treated with early and late radiotherapy (P=0.849)and between those with asymptomatic and those with symptomatic intracranial metastases (P=0.189).The OS and intracranial TTP of patients with intracranial oligometastases (≤3metastatic sites)were not significantly different from those of patients with multiple intracranial metastases (P=0.104 and P=0.357,respectively),and exon 19 and exon 21 mutations didn't show significant effects on the OS and intracranial TTP of patients (P=0.418 and P=0.386,respectively).In conclusion,there was no statistically significant difference in the OS between the EGFR-TKI alone group and EGFR-TK1 plus WBRT group.However, simultaneous use of WBRT was found to significantly prolong intracranial TTP and improve cerebral symptoms,and thus EGFR-TKI and WBRT combined may be clinically beneficial for patients with EGFR mutation-positive lung adenocarcinoma and brain metastases.

Is there a role for epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor wildtype non-small cell lung cancer?

Non-small cell lung cancer(NSCLC) is the most common type of lung cancer with a world-wide annual incidence of around 1.3 million. The majority of patients arediagnosed with advanced disease and survival remains poor. However, relevant advances have occurred in recent years through the identification of biomarkers that predict for benefit of therapeutic agents. This is exemplified by the efficacy of epidermal growth factor receptor(EGFR) tyrosine kinase inhibitors for the treatment of EGFR mutant patients. These drugs have also shown efficacy in unselected populations but this point remains controversial. Here we have reviewed the clinical data that demonstrate a small but consistent subgroup of EGFR wild-type patients with NSCLC that obtain a clinical benefit from these drugs. Moreover, we review the biological rationale that may explain this benefit observed in the clinical setting.

New era of epidermal growth factor receptor-tyrosine kinase inhibitors for lung cancer

Lung cancer is the leading cause of death globally, besides recent advances in its management; it maintains a low 5-year survival rate of 15%. The discovery of epidermal growth factor receptor(EGFR) activating mutations and the introduction of its tyrosine kinase inhibitors(TKIs) have expanded the treatment options for patients with non-small cell lung cancer. Nowadays, EGFR mutation testing is now a common routine for newly diagnosed lung cancer. First generation TKIs developed, erlotinib and gefitinib, were reversible ones. After a median of 14 mo, eventually all EGFR mutated patients develop resistance to reversible TKIs. Afatinib, dacomitinib and neratinib, second generation inhibitors, are selective and irreversible TKIs. Finally, third generation phase Ⅰclinical trials were performed, with lower toxicity profiles, and targeting with more precision the driving clone of this heterogeneous disease.

Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease

Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.

Coexistence of anaplastic lymphoma kinase rearrangement in lung adenocarcinoma harbouring epidermal growth factor receptor mutation:A single-center study

BACKGROUND Accumulating evidences confirm that epidermal growth factor receptor(EGFR)mutation and anaplastic lymphoma kinase(ALK)rearrangement have coexisted in lung adenocarcinoma(LUAD).However,Its biological mechanism,clinicopathological features,and optimization of targeted drugs have not yet been completely elucidated.AIM To explore the clinical profile of LUAD patients with co-mutations of EGFR and ALK genes,with hopes of scientifically guiding similar patients towards selected,targeted drugs.METHODS Two hundred and thirty-seven LUAD patients were enrolled.EGFR mutations were detected by the amplification refractory mutation system-peptide nucleic acid technique,while the expression of ALK rearrangement was screened by the 5′/3′imbalance strategy for reverse transcription followed by quantitative polymerase chain reaction analysis.The clinicopathological features of these patients were analysed retrospectively,and the follow-up data were collected.RESULTS There were six cases with co-mutations of EGFR and ALK genes,which were more common in women,non-smoking and stage IV LUAD patients with bone metastasis,hence a positive rate of 2.53%(6/237).EGFR-tyrosine kinase inhibitors(EGFR-TKIs)were their preferred drugs for targeted therapy in these patients,with progression-free survival ranging from two months to six months.CONCLUSION In Gannan region,the positive rate of co-mutations of EGFR and ALK genes in LUAD patients is relatively high,and the co-mutations are more common in women,non-smoking and stage IV patients with bone metastasis.These patients prefer EGFR-TKIs as their preferred targeted drugs,but the therapeutic effect is not good.EGFR/ALK dual-TKIs may be more effective targeted drugs,which needs further study.

Epidermal growth factor receptor inhibitors in colorectal cancer treatment: What's new?

Colorectal cancer constitutes one of the most common malignancies and the second leading cause of death from cancer in the western world representing one million new cases and half a million deaths annually worldwide. The treatment of patients with metastatic colon cancer comprises different regimens of chemotherapeutic compounds (fluoropyrimidines, irinotecan and oxaliplatin) and new targeted therapies. Interestingly, most recent trials that attempt to expose patients to all five-drug classes (fluoropyrimidines, irinotecan, oxaliplatin, bevacizumab and cetuximab) achieve an overall survival well over 2 years. In this review we will focus on the main epidermal growth factor receptor inhibitors demonstrating clinical benefit for colorectal cancer mainly cetuximab, panitumumab, erlotinib and gefitinib. We will also describe briefly the molecular steps that lie beneath them and the different clinical or molecular mechanisms that are reported for resistance and response.

Tyrosine kinase inhibitors:Multi-targeted or single-targeted?

Since in most tumors multiple signaling pathways are involved,many of the inhibitors in clinical development are designed to affect a wide range of targeted kinases.The most important tyrosine kinase families in the development of tyrosine kinase inhibitors are the ABL,SCR,platelet derived growth factor,vascular endothelial growth factor receptor and epidermal growth factor receptor families.Both multi-kinase inhibitors and singlekinase inhibitors have advantages and disadvantages,which are related to potential resistance mechanisms,pharmacokinetics,selectivity and tumor environment.In different malignancies various tyrosine kinases are mutated or overexpressed and several resistance mechanisms exist.Pharmacokinetics is influenced by interindividual differences and differs for two single targeted inhibitors or between patients treated by the same tyrosine kinase inhibitor.Different tyrosine kinase inhibitors have various mechanisms to achieve selectivity,while differences in gene expression exist between tumor and stromal cells.Considering these aspects,one type of inhibitor can generally not be preferred above the other,but will depend on the specific genetic constitution of the patient and the tumor,allowing personalized therapy.The most effective way of cancer treatment by using tyrosine kinase inhibitors is to consider each patient/tumor individually and to determine the strategy that specifically targets the consequences of altered(epi)genetics of the tumor.This strategy might result in treatment by a single multi kinase inhibitor for one patient,but in treatment by a couple of single kinase inhibitors for other patients.

Efficacy of EGFR Tyrosine Kinase Inhibitors in Non-small Cell Lung Cancer Patients Harboring Different Types of EGFR Mutations:A Retrospective Analysis

With the development of molecular pathology, many types of epidermal growth factor receptor（EGFR） mutations have been identified. The efficacy of EGFR tyrosine kinase inhibitors（EGFR-TKIs） in non-small cell lung cancer（NSCLC） patients with different types of EGFR mutations, especially in patients with single rare mutations or complex mutations（co-occurrence of two or more different mutations）, has not been fully understood. This study aimed to examine the efficacy of EGFR-TKIs in NSCLC patients with different types of EGFR mutations. Clinical data of 809 NSCLC patients who harbored different types of EGFR mutations and treated from January 2012 to October 2016 at Renmin Hospital and Zhongnan Hospital, Wuhan, were retrospectively reviewed. The clinical characteristics of these patients and the efficacy of EGFR-TKIs were analyzed. Among these patients, 377 patients had only the EGFR del-19 mutation, 362 patients the EGFR L858R mutation in exon 21, 33 patients single rare mutations and 37 patients complex mutations. Among these 809 patients, 239 patients were treated with EGFR-TKIs. In all the 239 patients, the disease control rate（DCR） was 93.7% with two patients（0.2%） achieving complete response（CR）, the median progression free survival（PFS） was 13.0 months（95% confidence interval [CI], 11.6–14.4 months）, and the median overall survival（OS） was 55.0 months（95% CI, 26.3–83.7 months）. Subgroup analysis revealed that the DCR in patients harboring single rare or complex mutations of EGFR was significantly lower than in those with del-19 or L858 R mutation（P〈0.001）. Patients with classic mutations（del-19 and/or L858 R mutations） demonstrated longer PFS（P〈0.001） and OS（P=0.017） than those with uncommon mutations（single rare and/or complex mutations）. Furthermore, the patients with single rare mutations had shorter median OS than in those with other mutations. Multivariate Cox regression analysis identified that the type of EGFR mutations was an independent risk factor for PFS（hazard ratio [HR]=0.308, 95% CI, 0.191–0.494, P〈0.001） and OS（HR=0.221, 95% CI, 0.101–0.480, P〈0.001）. The results suggest that the single rare or complex EGFR mutations confer inferior efficacy of EGFR-TKIs treatment to the classic mutations. The prognosis of the single rare EGFR mutations is depressing. EGFR-TKIs may be not a good choice for NSCLC patients with single rare mutations of EGFR. Further studies in these patients with uncommon mutations（especially for the patients with single rare mutations） are needed to determine a better precision treatment.

JAK3 inhibitor Ⅵ is a mutant specific inhibitor for epidermal growth factor receptor with the gatekeeper mutation T790M

AIM:To identify non-quinazoline kinase inhibitors effective against drug resistant mutants of epidermal growth factor receptor(EGFR).METHODS:A kinase inhibitor library was subjected to screening for specific inhibition pertaining to the in vitro kinase activation of EGFR with the gatekeeper mutation T790 M,which is resistant to small molecular weight tyrosine kinase inhibitors(TKIs) for EGFR in nonsmall cell lung cancers(NSCLCs). This inhibitory effect was confirmed by measuring autophosphorylation of EGFR T790M/L858 R in NCI-H1975 cells,an NSCLC cell line harboring the gatekeeper mutation. The effects of a candidate compound,Janus kinase 3(JAK3) inhibitor Ⅵ,on cell proliferation were evaluated using the MTT assay and were compared between T790M-positive and-negative lung cancer cell lines. JAK3 inhibitor Ⅵ was modeled into the ATP-binding pocket of EGFR T790M/L858 R. Potential physical interactions between the compound and kinase domains of wild-type(WT) or mutant EGFRs or JAK3 were estimated by calculating binding energy. The gatekeeper residues of EGFRs and JAKs were aligned to discuss the similarities among EGFR T790 M and JAKs. RESULTS:We found that JAK3 inhibitor Ⅵ,a known inhibitor for JAK3 tyrosine kinase,selectively inhibits EGFR T790M/L858 R,but has weaker inhibitory effects on the WT EGFR in vitro. JAK3 inhibitor Ⅵ also specifically reduced autophosphorylation of EGFR T790M/L858 R in NCI-H1975 cells upon EGF stimulation,but did not show the inhibitory effect on WT EGFR in A431 cells. Furthermore,JAK3 inhibitor Ⅵ suppressed the proliferationof NCI-H1975 cells,but showed limited inhibitory effects on the WT EGFR-expressing cell lines A431 and A549.A docking simulation between JAK3 inhibitor Ⅵ and the ATP-binding pocket of EGFR T790M/L858 R predicted a potential binding status with hydrogen bonds. Estimated binding energy of JAK3 inhibitor Ⅵ to EGFR T790M/L858 R was more stable than its binding energy to the WT EGFR. Amino acid sequence alignments revealed that the gatekeeper residues of JAK family kinases are methionine in WT,similar to EGFR T790 M,suggesting that TKIs for JAKs may also be effective for EGFR T790 M. CONCLUSION:Our findings demonstrate that JAK3 inhibitor Ⅵ is a gatekeeper mutant selective TKI and offer a strategy to search for new EGFR T790 M inhibitors.

参苓白术散联合EGFR-TKIs靶向治疗非小细胞肺癌临床观察

目的 参苓白术散联合人表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)靶向治疗非小细胞肺癌(NSCLC)的临床效果。方法 将患者随机分为对照组(29例)和联合组(30例)。对照组采用EGFR-TKIs靶向治疗,联合组在对照组基础上予口服参苓白术散。治疗9周,比较2组临床疗效、中医证候积分、免疫功能指标及不良反应发生率。结果 联合组临床疗效优于对照组(P<0.05)。治疗后,2组中医证候积分下降,联合组偏低(P<0.05);2组CD4^(+)、CD4^(+)/CD8^(+)比率升高,联合组偏高(P<0.05),CD8^(+)水平则降低,联合组偏低(P<0.05)。联合组不良反应总发生率低于对照组(P<0.05)。结论 参苓白术散联合EGFR-TKIs靶向治疗NSCLC疗效显著,可改善免疫功能,减轻不良反应。

Management of tyrosine kinase inhibitor resistance in lung cancer with EGFR mutation

The identification of driver mutations and drugs that inhibit their activity has been a major therapeutic advance for patients with advanced lung adenocarcinoma. Unfortunately, the success of these drugs is limited by the universal development of resistance. Treatment failure can result from inadequate drug exposure or selection of resistant malignant clones. Clinically distinct mechanisms of disease progression have been identified and can inform treatment decisions. Investigations into the biochemical mechanisms of tyrosine kinase inhibitor resistance may provide additional therapeutic targets by which the efficacy of targeted therapy can be improved.

The relationship between tyrosine kinase inhibitor therapy and overall survival in patients with non-small cell lung cancer carrying EGFR mutations

For patients with epidermal growth factor receptor (EGFR) mutation-positive lung cancer, the relationship between the dose or duration of treatment with tyrosine kinase inhibitor (TKI) and overall survival remains unclear. Here, we analyzed clinical data of 39 patients who were diagnosed with EGFR mutation-positive non-small cell lung cancer and treated with TKI, but subsequently died. Several parameters were measured in this study: overall survival; first, second, and overall TKI therapy durations; first TKI intensity (actual dose/normal dose); and TKI rate (overall TKI therapy duration/overall survival). The response rate to TKI therapy was 50% , and the median survival was 553 days. After TKI therapy failed, 38.5% patients were re-challenged with TKI. We observed a moderate relationship [r = 0.534, 95% confidential interval (CI) = 0.263 to 0.727, P < 0.001] between overall TKI therapy duration and overall survival. However, we found no relationship between overall survival and first TKI intensity (r = 0.073, 95% CI = -0.380 to 0.247, P = 0.657) or TKI rate (r = 0.0345, 95% CI = -0.284 to 0.346, P = 0.835). Nonsmall cell lung cancer patients with mutation-positive tumors remained on TKI therapy for, on average, 33% of the overall survival time. These findings suggest that patients with EGFR mutation-positive tumors should not stick to using TKIs.

Targeting receptor tyrosine kinases in gastric cancer

Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials.One group of representative targeted oncogenic kinases,the receptor tyrosine kinases(RTKs),has been associated with gastric cancer development.Trastuzumab,an inhibitor of ERBB2,has been approved for the treatment of gastric cancer,although other receptor tyrosine kinases,such as epidermal growth factor receptor,vascular endothelial growth factor,platelet-derived growth factor receptor,c-Met,IGF-1R and fibroblast growth factor receptor 2,are also activated in gastric cancer.The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients.On the other hand,the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients;however,a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial.Other clinical trials,especially phaseⅢtrials that have tested drugs targeting RTKs,such as cetuximab,panitumumab,gefitinib,erlotinib,figitumumab,sorafenib,sunitinib and lapatinib,have shown that these drugs have modest effects against gastric cancer.This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.

Associations Between Epidermal Growth Factor Receptor Gene Mutation and Serum Tumor Markers in Advanced Lung Adenocarcinomas: A Retrospective Study

Objective To investigate the associations between epidermal growth factor receptor(EGFR) gene mutations and serum tumor markers in advanced lung adenocarcinomas. Methods We investigated the association between EGFR gene mutations and clinical features, including serum tumor marker levels, in 97 advanced lung adenocarcinomas patients who did not undergo the treatment of EGFR tyrosine kinase inhibitors. EGFR gene mutation was detected by real-time PCR at exons 18, 19, 20, and 21. Serum tumor marker concentrations were analyzed by chemiluminescence assay kit at the same time. Results EGFR gene mutations were detected in 42(43%) advanced lung adenocarcinoma patients. Gender(P=0.003), smoking status(P=0.001), and abnormal serum status of carcinoembryonic antigen(CEA, P=0.028) were significantly associated with EGFR gene mutation incidence. Multivariate analysis showed the abnormal CEA level in serum was independently associated with the incidence of EGFR gene mutation(P=0.046) with an odds ratio of 2.613(95% CI: 1.018-6.710). However, receiver operating characteristic(ROC) curve analysis revealed CEA was not an ideal predictive marker for EGFR gene mutation status in advanced lung adenocarcinoma(the area under the ROC curve was 0.608, P=0.069). Conclusions EGFR gene mutation status is significantly associated with serum CEA status in advanced lung adenocarcinmoas. However, serum CEA is not an ideal predictor for EGFR mutation.

The efficacy of Kanglaite injection during treatment with tyrosine kinase inhibitor in elderly patients with non-small cell lung cancer

Objective Epidermal growth factor receptor–tyrosine kinase inhibitors(EGFR–TKIs) are widely used in the treatment of EGFR mutation-positive non-small cell lung cancer(NSCLC) patients. The Kanglaite injection(KLT) is a novel broad-spectrum anti-cancer injection produced from traditional Chinese medicinal herbs(coix seed). After its approval in 1995, KLT has become the most popular anti-cancer drug in China. As of this writing, no standard treatment guideline is available for elder patients with NSCLC, and the role of traditional Chinese medicinal herbs, including KLT, combined with TKI treatment remains unknown. This retrospective study evaluated the efficacy and safety of KLT in elderly NSCLC patients during TKI treatment.Methods Thirty elderly patients aged 71-79 years with histopathologically confirmed NSCLC attending the General Hospital of the Shenyang Military Region were enrolled in the study and received EGFR-TKI treatment. All participants received 200 m L KLT injections at the same time on days 1–21. Erlotinib(150 mg) or gefitinib(250 mg) was administered daily from days 1 to 21, and the cycle was repeated every 21 days. The endpoint of the primary study was the disease control rate.Results Thirty elderly patients were enrolled in this study. The objective response rate was 21.3% [95% confidence interval(CI): 8.6% to 35.2%], whereas the disease control rate was 80.4%(95% CI: 71.8% to 97.0%). The grade 3 or 4 adverse effects included leucopenia(13.7%), neutropenia(13.4%), anemia(2.9%), and nausea or vomiting(2.7%). Conclusion The administration of KLT combined with erlotinib or gefitinib showed high efficacy in elderly NSCLC patients. The adverse effects of the drug combination were well tolerated by the patients. KLT combined with TKI treatment might provide a satisfactory therapeutic strategy for elderly NSCLC patients.

EGFR突变的晚期肺腺癌患者EGFR-TKIs治疗过程中脑转移的危险因素分析

目的 评估表皮生长因子受体(EGFR)突变的晚期肺腺癌患者酷氨酸激酶抑制剂(EGFR-TKIs)治疗过程中脑转移的危险因素研究,为临床诊治提供参考。方法 回顾性分析2018年1月至2020年1月收治的134例EGFR突变晚期肺腺癌患者的临床资料,均随访至2023年4月30日。用Kaplan-Meier法计算脑转移的累积发病率,用多因素Cox回归分析脑转移的独立危险因素。结果 34例患者(25.4%)在EGFR-TKIs治疗过程中发生脑转移。多因素分析显示年龄≤53岁(HR:2.751,95%CI:1.326~5.707;P=0.007)、血清癌胚抗原≥23 ng/mL(HR:3.197,95%CI:1.512~6.758;P=0.002)和EGFR21外显子突变(HR:2.769,95%CI:1.355~5.659;P=0.005)是发生脑转移的独立高危因素。结论 EGFR突变的晚期肺腺癌患者EGFR-TKIs治疗过程中脑转移的危险因素较多,临床上值得注意。

基于生物信息学筛选与铁死亡有关的非小细胞肺癌EGFR-TKIs耐药DEGs

目的基于生物信息学筛选与铁死亡有关的非小细胞肺癌(NSCLC)表皮生长因子受体(EGFR)-酪氨酸激酶抑制剂(TKIs)耐药差异表达基因(DEGs)。方法从基因表达综合数据库(GEO)中选取NSCLC EGFR-TKIs耐药的细胞测序基因集GSE117846,从中筛选P<0.05且|log 2FC|≥1(FC表示变化倍数)的DEGs。利用FerrDb数据库获取铁死亡相关基因。采用jvenn对从GSE117846数据集中筛选得到的DEGs与从FerrDb数据库中获取的铁死亡相关基因取交集。对交集基因进行基因本体论(GO)功能和京都基因与基因组百科全书(KEGG)通路富集分析,并绘制蛋白质-蛋白质相互作用(PPI)网络。采用Cytoscape软件中的Cytohubba插件计算交集基因的评分,取评分前10的基因用于Hub基因的筛选。利用ULCAN和GEPIA2数据库分析Hub基因在NSCLC中的表达及对患者生存预后的影响。通过实时荧光定量PCR(qPCR)检测Hub基因mRNA在NSCLC患者癌组织和癌旁组织及体外细胞中的相对表达水平,验证生物信息学的分析结果。结果共筛选获得60个与铁死亡有关的NSCLC EGFR-TKIs耐药DEGs,包括30个上调基因和30个下调基因。这60个基因主要富集在P53信号通路、铁死亡通路、FoxO信号通路。PPI网络中有57个节点和99条边,平均聚类系数为0.377,PPI富集P<0.01。Cytohubba插件筛选得到的Hub基因为肿瘤蛋白P63(TP63)。ULCAN和GEPIA2数据库分析显示,肺腺癌组织中的TP63表达水平低于正常组织,而肺鳞癌组织中的TP63表达水平高于正常组织,差异均有统计学意义(P<0.05);在肺腺癌患者中,TP63高、低表达组的生存预后比较,差异无统计学意义(P>0.05),而在肺鳞癌患者中,TP63低表达组的生存预后较好,差异有统计学意义(P<0.05)。qPCR检测显示,与癌旁组织相比,TP63 mRNA在肺鳞癌组织中高表达,在肺腺癌组织中低表达,差异均有统计性意义(P<0.05);在体外细胞中检测到TP63 mRNA在对吉非替尼耐药的PC9/GR细胞中表达下调(P<0.05),与生物信息学的分析结果一致。结论TP63可能为连接NSCLC EGFR-TKIs耐药与铁死亡的重要基因。

Clinical Benefit of Epidermal Growth Factor Receptor-Tyrosine Kinase Inhibitors Plus Radiotherapy for Epidermal Growth Factor Receptor-Mutated Metastatic Non-Small Cell Lung Cancer: A Retrospective Analysis on Real World Data

Objective: To investigate the benefit of epidermal growth factor receptor( EGFR) tyrosine kinase inhibitors( TKIs)with radiotherapy in patients with EGFR mutation-positive metastatic non-small cell lung cancer( NSCLC),compared with TKIs alone.Methods: A total of 103 patients with stage Ⅳ EGFR-mutated NSCLC treated from February 2015 to May 2017 at Sichuan Cancer Hospital were analyzed retrospectively. Fifty patients were treated with EGFR-TKIs( gefitinib or erlotinib) plus radiotherapy( the TKI +RT group) and 53 patients received EGFR-TKIs alone( the TKI group). Tumor response,survival and toxicities were compared between the two groups. Results: Median follow-up time was 11. 7 months( 2. 8-36. 3 months). The overall response rate( ORR) and disease control rate( DCR) in the TKI + RT group vs the TKI group were 62% vs 37. 7%( P = 0. 014) and 88% vs 75. 5%( P =0. 101),respectively. The median progression-free survival( PFS) and median overall survival( OS) in the TKI + RT group were superior to those of the TKI group( 18. 87 months vs 12. 80 months,P = 0. 035 and 23. 10 months vs 18. 30 months,P = 0. 011). OS rates in the TKI + RT group and the TKI group were 56. 0% vs 35. 8% at year 1( P = 0. 04) and 16. 0% vs 3. 8% at year 2( P =0. 036). Multivariate Cox model found that TKI + RT related to significantly better OS( hazard ratio = 0. 209;95% CI,0. 066 to0. 661;P = 0. 008) than TKI alone. Adverse events did not differ significantly between the two groups( P > 0. 050). Conclusion:Compared with EGFR-TKIs alone,EGFR-TKIs combined with radiotherapy was well tolerated and showed benefit in tumor response and survival for EGFR mutation-positive metastatic NSCLC patients.