[Study Progression on Non-small Cell Lung Cancer with EGFR Mutation
Treated by Immune Checkpoint Inhibitors].
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In recent years, epidermal growth factor receptor tyrosine kinase inhibitors have been recommended by many guidelines as first-line drugs for advanced non-small cell lung cancer (NSCLC) with EGFR gene mutations and no resistance. However, with the prolongation of medication time, most appear acquired resistance. In recent years, breakthroughs in inhibitors of programmed death-1 (PD-1) and its ligand (PD1 ligand, PD-L1) have rapidly changed the therapeutic model of NSCLC. Recent studies have shown that the efficacy of immune checkpoint inhibitors in EGFR-mutant NSCLC patients is not satisfactory, which might be caused by low PD-L1 expression, inhibitory immune microenvironment and low tumor mutation load. This review will elaborate the immune microenvironment of NSCLC patients with EGFR mutation, the latest study progression of immune checkpoint inhibitors and its combined with TKI, expecting to bring new hopes for the treatment of EGFR-mutant NSCLC patients. .【中文题目：免疫检查点抑制剂治疗EGFR突变非小细胞 肺癌的研究进展】 【中文摘要：近年来，表皮生长因子受体酪氨酸激酶抑制剂（epidermal growth factor receptor tyrosine kinase inhibitor, EGFR-TKI）已被多项指南推荐作为表皮生长因子受体（epidermal growth factor receptor, EGFR）基因敏感突变且不存在耐药的晚期非小细胞肺癌（non-small cell lung cancer, NSCLC）的一线治疗药物，但随着用药时间的延长，大多数患者出现获得性耐药。近几年，针对免疫检查点程序死亡受体（programmed death-1, PD-1）及其配体（PD-1 ligand, PD-L1）的抑制剂取得突破性进展，迅速改变着NSCLC的治疗模式。而近期研究显示，EGFR突变NSCLC患者免疫检查点抑制剂疗效尚不理想，可能机制主要包括PD-L1低表达、抑制性免疫微环境及低肿瘤突变负荷等。通过对EGFR突变NSCLC患者免疫微环境的变化情况，免疫检查点抑制剂及其与TKI联合应用的研究进展的系列分析，有望为EGFR突变NSCLC患者的治疗带来新希望。 】 【中文关键词：免疫检查点抑制剂；肺肿瘤；表皮生长因子受体基因突变；程序性死亡配体-1】.Keywords:
EGFR Inhibitors
Immune checkpoint
Treatment strategies involving immune-checkpoint blockade (ICB) have significantly improved survival for a subset of patients across a broad spectrum of advanced solid cancers. Despite this, considerable room for improving response rates remains. The tumor microenvironment (TME) is a hurdle to immune function, as the altered metabolism-related acidic microenvironment of solid tumors decreases immune activity. Here, we determined that expression of the hypoxia-induced, cell-surface pH regulatory enzyme carbonic anhydrase IX (CAIX) is associated with worse overall survival in a cohort of 449 patients with melanoma. We found that targeting CAIX with the small-molecule SLC-0111 reduced glycolytic metabolism of tumor cells and extracellular acidification, resulting in increased immune cell killing. SLC-0111 treatment in combination with immune-checkpoint inhibitors led to the sensitization of tumors to ICB, which led to an enhanced Th1 response, decreased tumor growth, and reduced metastasis. We identified that increased expression of CA9 is associated with a reduced Th1 response in metastatic melanoma and basal-like breast cancer TCGA cohorts. These data suggest that targeting CAIX in the TME in combination with ICB is a potential therapeutic strategy for enhancing response and survival in patients with hypoxic solid malignancies.
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Fifteen percent of lung cancer cases occur in never-smokers and show characteristics that are molecularly and clinically distinct from those in smokers. Epidermal growth factor receptor (EGFR) gene mutations, which are correlated with sensitivity to EGFR-tyrosine kinase inhibitors (EGFR-TKIs), are more frequent in never-smoker lung cancers. In this study, microRNA (miRNA) expression profiling of 28 cases of never-smoker lung cancer identified aberrantly expressed miRNAs, which were much fewer than in lung cancers of smokers and included miRNAs previously identified (e.g., up-regulated miR-21) and unidentified (e.g., down-regulated miR-138) in those smoker cases. The changes in expression of some of these miRNAs, including miR-21, were more remarkable in cases with EGFR mutations than in those without these mutations. A significant correlation between phosphorylated-EGFR (p-EGFR) and miR-21 levels in lung carcinoma cell lines and the suppression of miR-21 by an EGFR-TKI, AG1478, suggest that the EGFR signaling is a pathway positively regulating miR-21 expression. In the never-smoker-derived lung adenocarcinoma cell line H3255 with mutant EGFR and high levels of p-EGFR and miR-21, antisense inhibition of miR-21 enhanced AG1478-induced apoptosis. In a never-smoker-derived adenocarcinoma cell line H441 with wild-type EGFR, the antisense miR-21 not only showed the additive effect with AG1478 but also induced apoptosis by itself. These results suggest that aberrantly increased expression of miR-21, which is enhanced further by the activated EGFR signaling pathway, plays a significant role in lung carcinogenesis in never-smokers, as well as in smokers, and is a potential therapeutic target in both EGFR-mutant and wild-type cases.
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The success in lung cancer therapy with programmed death (PD)-1 blockade suggests that immune escape mechanisms contribute to lung tumor pathogenesis. We identified a correlation between EGF receptor (EGFR) pathway activation and a signature of immunosuppression manifested by upregulation of PD-1, PD-L1, CTL antigen-4 (CTLA-4), and multiple tumor-promoting inflammatory cytokines. We observed decreased CTLs and increased markers of T-cell exhaustion in mouse models of EGFR-driven lung cancer. PD-1 antibody blockade improved the survival of mice with EGFR-driven adenocarcinomas by enhancing effector T-cell function and lowering the levels of tumor-promoting cytokines. Expression of mutant EGFR in bronchial epithelial cells induced PD-L1, and PD-L1 expression was reduced by EGFR inhibitors in non-small cell lung cancer cell lines with activated EGFR. These data suggest that oncogenic EGFR signaling remodels the tumor microenvironment to trigger immune escape and mechanistically link treatment response to PD-1 inhibition.We show that autochthonous EGFR-driven lung tumors inhibit antitumor immunity by activating the PD-1/PD-L1 pathway to suppress T-cell function and increase levels of proinflammatory cytokines. These findings indicate that EGFR functions as an oncogene through non-cell-autonomous mechanisms and raise the possibility that other oncogenes may drive immune escape.
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Many attempts have been made to find genetic abnormalities inducing carcinogenesis after the development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor targeting EGFR in lung cancer. New target therapies have been already commercialized and studied along with the recent discovery of gene rearrangement involved in the carcinogenic process of non-small cell lung cancer. This study aims to investigate anplastic lymphoma kinase, c-ros oncogene 1, and receptor tyrosine kinase, in particular. Keywords: Lung Neoplasms; Anplastic Lymphoma Kinase; ROS1 Protein, Human
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The discovery of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in patient with activating mutations in the EGFR gene in 2004 dramatically altered the approach to the treatment of non-small cell lung cancer (NSCLC) (1,2). However, the path to the current treatment paradigm for the use of EGFR TKIs in patients with NSCLC has been circuitous. The first (and to date only) regulatory approval of EGFR inhibitors for NSCLC in the United States was based on data from the BR.21 trial.
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c-MET is considered a promising oncogenic driver in non-small cell lung cancer (NSCLC) after the discovery of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK). MET activation including gene mutation, amplification and protein overexpression, all of these are potential therapeutic targets and are associated with poor prognosis. Clinical evidence suggests a role for MET activation as both a primary oncogenic driver in subsets of lung cancer, and as a secondary driver of acquired resistance to EGFR-tyrosine kinase inhibitor (TKI). This review focuses on the MET activation in NSCLC and the latest trials of its treatment.c-MET被认为是继表皮生长因子受体（epidermal growth factor receptor, EGFR）基因突变和间变性淋巴瘤激酶（anaplastic lymphoma kinase, ALK）基因融合之后，非小细胞肺癌（non-small cell lung cancer, NSCLC）又一个重要的驱动基因。MET的激活包括突变、扩增和蛋白质过表达，是NSCLC潜在的治疗靶点，并提示与预后相关。临床证据表明，MET既可以作为肺癌的原发致癌驱动基因，也是EGFR靶向治疗获得性耐药的原因之一。本文主要对c-MET通路在NSCLC中的活性形式及治疗的研究进展进行综述。.
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In patients with advanced non-small cell lung cancer (NSCLC) whose tumour harbour a sensitising epidermal growth factor receptor (EGFR) mutation, international guidelines recommend first-line therapy with an EGFR tyrosine kinase inhibitor (TKI) due to longer progression free survival (PFS), higher overall response rate (ORR) and improved quality of life compared to platinum doublet chemotherapy (1,2).
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Background: Lung cancer is the most common type of cancer to spread to the brain (brain metastasis [BM]). This study assessed the effect of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in combination with whole-brain radiotherapy (WBRT) on EGFR -mutant non-small-cell lung cancer (NSCLC) patients with BM. Patients and methods: Thirty-nine patients, who had receieved different EGFR TKIs plus 30 Gy WBRT until disease progression, were retrospectively analyzed between 2010 and 2014. Treatment response was evaluated and survival data were collected and analyzed. Results: Among the 39 patients, 18 had an EGFR exon 19 deletion and 21 had an EGFR exon 21 point mutation. After therapy, 19 (48.7%) patients had complete remission, 12 (30.8%) had partial remission, and eight (20.5%) had stable disease in the intracranial lesions. Besides, there was no single case of complete remission, 21 (53.8%) had partial remission, and 18 (46.2%) had stable disease of the extracranial lesions. The median progression-free survival (PFS) of intracranial lesions and extracranial lesions was 18 and 12 months, respectively. The median overall survival (OS) was 26 months. The univariate analysis showed that graded prognostic assessment ( P =0.006) and Karnofsky Performance Scale ( P =0.045) were associated with intracranial progression-free survival (iPFS), while recursive partitioning analysis ( P =0.049) was associated with OS of patients. Conclusion: EGFR TKIs plus concomitant WBRT controlled intracranial lesions of lung cancer metastasis and significantly improved OS of patients. Further studies will be needed to confirm whether this combination treatment could be used as a standard therapy for EGFR -mutated NSCLC patients with BM. Keywords: non-small-cell lung cancer, brain metastases, epidermal growth factor receptor, tyrosine kinase inhibitors, whole-brain radiotherapy
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Abstract The epidermal growth factor receptor (EGFR) family of receptor tyrosine kinases, including EGFR, HER2/erbB2, and HER3/erbB3, is an attractive target for antitumor strategies. Aberrant EGFR signaling is correlated with progression of various malignancies, and somatic tyrosine kinase domain mutations in the EGFR gene have been discovered in patients with non–small cell lung cancer responding to EGFR-targeting small molecular agents, such as gefitinib and erlotinib. EGFR overexpression is thought to be the principal mechanism of activation in various malignant tumors. Moreover, an increased EGFR copy number is associated with improved survival in non–small cell lung cancer patients, suggesting that increased expression of mutant and/or wild-type EGFR molecules could be molecular determinants of responses to gefitinib. However, as EGFR mutations and/or gene gains are not observed in all patients who respond partially to treatment, alternative mechanisms might confer sensitivity to EGFR-targeting agents. Preclinical studies showed that sensitivity to EGFR tyrosine kinase inhibitors depends on how closely cell survival and growth signalings are coupled with EGFR, and also with HER2 and HER3, in each cancer. This review also describes a possible association between EGFR phosphorylation and drug sensitivity in cancer cells, as well as discussing the antiangiogenic effect of gefitinib in association with EGFR activation and phosphatidylinositol 3-kinase/Akt activation in vascular endothelial cells.
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