MEK抑制剂在EGFR-TKI靶向治疗非小细胞肺癌中的作用

非小细胞肺癌是最常见的肺癌,最常见的基因突变是EGFR突变,EGFR-TKI已被用于治疗含这类突变的患者。然而,随着治疗进展,患者逐渐出现耐药性导致治疗失败。主要原因是EGFR信号通路下游重新激活,其中RAS/RAF/MEK/ERK和PI3K/AKT/PKC途径最重要。ERK1/2信号再激活可产生对EGFR抑制剂的抗性。目前临床研究已经发现,MEK抑制剂可以抑制ERK磷酸化,从而阻止随后的MAP激酶下游磷酸化,并因此诱导肿瘤活动的退化和停滞。大量试验表明,ERK途径的持续激活有助于获得吉非替尼耐药性。MEK抑制剂还可以诱导细胞周期阻滞和凋亡。本文总结了MEK抑制剂和EGFR-TKI的作用及其在NSCLC治疗中的作用,为肺癌分子靶向治疗提供了新思路。     

Clinicopathologic Features and Immune Microenvironment of Non–Small-cell Lung Cancer With Primary Resistance to Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors

Background

Approximately 20% to 30% of non–small-cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR)-activating mutations are not responsive to EGFR tyrosine kinase inhibitors (TKIs). Although primary resistance to EGFR-TKIs has been attributed to various genetic alterations, little is known about the clinical and immunopathologic features of patients with primary resistance. The tumor immune microenvironment, including tumor-infiltrating lymphocytes (TILs) and programmed cell death ligand 1 (PD-L1), has been reported to play an important role in tumor progression in those with NSCLC. However, few studies have directly focused on the relationship between the tumor immune microenvironment and primary resistance to EGFR-TKIs.

Clinical Implications of the BIM Deletion Polymorphism in Advanced Lung Adenocarcinoma Treated With Gefitinib

Background

Proapoptotic protein Bcl-2–like 11 (BIM) is a crucial tumor suppressor gene in lung cancer development. A 2903-bp genomic deletion polymorphism is present in BIM intron 2, which alters RNA splicing and impairs the generation of the death-inducing isoform of BIM and resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). In the present study, we investigated the clinical implications of this genetic polymorphism in patients with advanced lung adenocarcinoma treated with gefitinib.

Mutation abundance affects the therapeutic efficacy of EGFR-TKI in patients with advanced lung adenocarcinoma: A retrospective analysis

Purpose: To investigate the influence of mutation abundance and sites of epidermal growth factor receptor (EGFR) on therapeutic efficacies of EGFR-tyrosine kinase inhibitor (EGFR-TKIs) treatments of patients with advanced non-small cell lung carcinoma (NSCLC).

Methods: EGFR mutational sites and mutation abundance were analyzed by amplification refractory mutation system (ARMS) in paraffin-embedded tissue sections taken from primary or metastatic tumors of 194 NSCLC patients.

Results: The median progression-free survival (PFS) time of the enrolled patients was 9.3 months (95% CI, 8.2–10.8 months). The PFS was significantly different with EGFR gene mutation abundance after EGFR-TKI therapy (P = 0.014). The median PFS was significantly longer when the cut-off value of EGFR mutation abundance of exon 19 or exon 21, and solely exon 19 was > 26.7% and 61.8%, respectively. For patients who received EGFR-TKI as first-line treatment, the median PFS was significantly longer in the high mutation abundance group than in the low mutation abundance group (12.7 vs 8.7 months, P = 0.002).

Conclusion: The PFS benefits were greater in patients with a higher abundance of exon 19 deletion mutations in the EGFR gene after EGFR-TKI treatment and first line EGFR-TKI treatment led to improved PFS in high mutation abundance patients.     

细胞自噬与EGFR抑制剂在肿瘤治疗中的研究进展

表皮生长因子受体(EGFR)抑制剂是近些年来肿瘤治疗的新策略。然而,先天性或者获得性耐药问题成为其疗效的一大障碍。自噬,是一种细胞自我消化的过程,并与耐药具有相关性。EGFR的激活能够通过多种信号通路调节自噬过程。EGFR抑制剂能够诱导自噬,然而EGFR诱导自噬的这种特殊作用是双向的。一方面,自噬能够增强EGFR抑制剂的细胞毒性作用,从而成为一种细胞的保护措施;另一方面,EGFR抑制剂治疗后产生的高自噬水平同样能够导致细胞自吞噬性死亡,从而逃脱凋亡,当EGFR抑制剂与一种自噬诱导剂联合应用时可能会产生更显著的治疗作用。因此,调节自噬水平将成为提高肿瘤患者EGFR抑制剂治疗效果的可行之举。     

口服EGFR-TKI药物治疗老年非小细胞肺癌的系统评价

目的：系统评价使用EGFR-TKI药物一线治疗非选择性老年晚期非小细胞肺癌患者的有效性及安全性。方法使用计算机对Cochrane图书馆、PubMed、Embase、CNKI、CBM等数据库(截止2015年4月)进行检索,从中纳入所有随机对照试验,进行系统评价。结果纳入3篇文献、共326例老年晚期非小细胞肺癌患者进入Meta-分析,结果显示：厄洛替尼或吉非替尼与长春瑞宾、紫杉醇单药或双药联合化疗等治疗方案相比,有效率(RR=0.91,95%CI：0.56~1.49,P=0.72)及肿瘤控制率均差异无统计学意义(RR=0.96,95%CI：0.79~1.17,P=0.68),且在中位无疾病进展时间及中位生存时间等方面差异无统计学意义。EGFR-TKI药物主要不良反应为皮疹、腹泻,其消化道和血液系统毒性与化疗相比较轻。结论在未行基因检测的非选择性老年晚期NSCLC患者中给予口服EGFR-TKI药物(吉非替尼或厄洛替尼)安全性较好,可获得与化疗药物相似疗效。     

晚期非小细胞肺癌EGFR-TKIs获得性耐药后治疗策略研究进展

肺癌是癌症相关死亡的首要原因。非小细胞肺癌（NSCLC）约占肺癌的85%,且患者在诊断时大多为晚期。随着表皮生长因子受体（EGFR）在肺癌中被发现,针对特定基因突变的靶向治疗成为晚期NSCLC的重要治疗方式,并显著延长了患者生存期。尽管第一、二、三代EGFR-酪氨酸激酶抑制剂（TKI）蓬勃发展,但随着治疗时间的推移,患者都可能面临耐药和进展。为克服这一难题,基于耐药机制的相关治疗策略正在研究中。本文旨在对近年来EGFR-TKIs,特别是在疗效及安全性上作为指南更优推荐的第三代EGFR-TKIs的耐药机制和治疗策略的研究进展进行综述。     

Sequential Administration of EGFR-TKI and Pemetrexed Achieved a Long Duration of Response in Advanced NSCLC Patients with EGFR-mutant Tumours

Objectives: The optimal combination of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors(TKIs) and chemotherapy has helped to improve therapeutic effects in non-small-cell lung cancer (NSCLC). This studyaimed to explore the progression free survival (PFS) of patients after sequential administration of TKI and pemetrexedchemotherapy. Methods: This study retrospectively screened treatment-naive advanced NSCLC patients harbouringEGFR mutations who were prescribed a TKI and salvaged with pemetrexed chemotherapy or vice versa. The total,initial and salvage PFS were collected. Results: The total PFS including both the initial and salvage PFS was 18.0 mon(95% CI: 14.1–21.9 mon), which was not influenced by the sequence of administration (TKI first: 18.0 mon, 95% CI:15.8–20.2 mon, pemetrexed first: 16.1 mon, 95% CI: 9.1–23.1 mon, HR 0.92, P=0.748). A longer PFS was achievedfor TKI over chemotherapy in both the initial (10.6 and 5.9 mon, HR 2.62, P=0.001) and salvage therapy (12.0 and 6.0mon, HR 1.29, P=0.001). TKI remained effective either before (10.6 mon) or after (12.0 mon) chemotherapy (HR 0.96,P=0.853). The same trend was observed for chemotherapy (5.9 and 6.0 mon for initial and salvage therapy, respectively,HR 0.82, P=0.417). Conclusions: The sequential administration of TKI and pemetrexed chemotherapy achieved a longPFS and was a suitable treatment for advanced NSCLC.     

Responses to crizotinib can occur in c-MET overexpressing nonsmall cell lung cancer after developing EGFR-TKI resistance

Evidence suggests that activation of the MET signaling pathway might be associated with EGFR-TKI resistance. EGFR TKI-resistant lung cancers often remain sensitive to inhibition of the EGFR pathway; thus, c-MET inhibitors are likely to be effective when combined with continued EGFR-TKI treatment. Here, we described a 56-year-old male who became refractory after first-line gefitinib therapy and was confirmed to have c-MET overexpression without a T790M mutation, c-MET amplification or MET exon 14 alterations. A complete response to crizotinib occurred in this patient. Our case report uncovered the underlying mechanism of c-MET overexpression in affecting EGFR-TKI sensitivity, and crizotinib may assist in overcoming this problem.     

A Multicenter Double-blind Phase II Study of Metformin With Gefitinib as First-line Therapy of Locally Advanced Non–Small-cell Lung Cancer

We present the rationale and study design of the CGMT (combined gefitinib and metformin therapy) trial (www.ClinicalTrials.gov Identifier: NCT01864681), which is aimed at treating locally advanced non–small-cell lung cancer. The CGMT trial is a multicenter, phase II randomized, double-blinded, and placebo-controlled study, which is designed to evaluate the safety and efficacy of metformin in combination with gefitinib as first-line therapy in patients presenting with stage IIIb-IV non–small-cell lung cancer expressing the epidermal growth factor receptor mutant. Two therapies are proposed for this trial. The first regimen is comprised of gefitinib plus metformin. The second therapy is comprised of gefitinib plus placebo. The primary objective of this trail is to compare the progression-free survival rate at year 1 of the study. The secondary objective of this trial is to compare the 2-year overall survival, the 2-year progression-free survival, the objective response rate, and the disease-control rate, and to evaluate the relative safety of both therapies. Based on the statistical design, we plan to enroll approximately 200 patients.