Challenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer

Lung cancer causes the highest mortality compared to other cancers in the world according to the latest WHO reports. Non-small cell lung cancer (NSCLC) contributes about 85% of total lung cancer cases. An extensive number of risk factors are attributed to the progression of lung cancer. Epidermal growth factor receptor (EGFR), one of the most frequently mutant driver genes, is closely involved in the development of lung cancer through regulation of the PI3K/AKT and MAPK pathways. As a representative of precision medicine, EGFR-tyrosine kinase inhibitors (TKIs) targeted therapy significantly relieves the development of activating mutant EGFR-driven NSCLC. However, treatment with TKIs facilitates the emergence of acquired resistance that continues to pose a significant hurdle with respect to EGFR targeted therapy. In this review, the development of current approved EGFR-TKIs as well as the related supporting clinical trials are summarized and discussed. Mechanisms of action and resistance were addressed respectively, which serve as important guides to understanding acquired resistance. We also explored the corresponding combination treatment options according to different resistance mechanisms. Future challenges include more comprehensive characterization of unclear resistance mechanisms in different populations and the development of more efficient and precision synthetic therapeutic strategies.     

Beyond chemotherapy and targeted therapy: adoptive cellular therapy in non-small cell lung cancer

Non-small cell lung cancer (NSCLC) is an intractable disease for which effective treatment approaches are urgently needed. The ability to induce antigen-specific immune responses in patients with lung cancer has led to the development of immunotherapy as a novel concept for the treatment of NSCLC. Adoptive cellular therapy (ACT) represents an important advancement in cancer immunotherapy with the utilization of tumor infiltrating lymphocytes, cytokine-induced killer cells, natural killer cells and γδ T cells. In this study, we review recent advances in ACT for NSCLC in clinical trials and provide a perspective on the improvement in ACT and potential therapeutic approaches using engineered T cell therapy for NSCLC.     

非小细胞肺癌靶向治疗的临床前研究进展

针对表皮生长因子受体（EGFR）和血管生成（angiogenesis）信号通路的靶向治疗已经在晚期非小细胞肺癌的治疗上取得成功,但由于抗药性的存在,大多数晚期患者的生存时间仍然提高有限。继发性的EGFR T790M突变和原癌基因肝细胞生长因子受体（MET）的扩增被鉴定为两种主要的抗药机制。最近转化生长因子-β（TGF-β）/白介素-6信号通路被报道能介导选择性和适应性地对erlotinib的抗药。另一方面,Kras突变所致肺癌的靶向治疗方面也取得了一些进展。双重抑制磷脂酰肌醇3-激酶（PI3K）和促分裂素原活化蛋白激酶激酶（MEK）信号通路可导致Kras突变肿瘤的显著消退,联合抑制SRC、PI3K和MEK可使丝氨酸/苏氨酸蛋白激酶11（Lkb1）缺失,Kras突变的肺癌小鼠的肿瘤明显消退,抑制核因子-κB（NF-κB）信号通路导致p53缺失,Kras突变的肿瘤发展显著减慢。这些发现都为发展非小细胞肺癌患者的靶向治疗提供了有力的支持。     

Identification of novel deregulated RNA metabolism-related genes in non-small cell lung cancer

Lung cancer is a leading cause of cancer death worldwide. Several alterations in RNA metabolism have been found in lung cancer cells; this suggests that RNA metabolism-related molecules are involved in the development of this pathology. In this study, we searched for RNA metabolism-related genes that exhibit different expression levels between normal and tumor lung tissues. We identified eight genes differentially expressed in lung adenocarcinoma microarray datasets. Of these, seven were up-regulated whereas one was down-regulated. Interestingly, most of these genes had not previously been associated with lung cancer. These genes play diverse roles in mRNA metabolism: three are associated with the spliceosome (ASCL3L1, SNRPB and SNRPE), whereas others participate in RNA-related processes such as translation (MARS and MRPL3), mRNA stability (PCBPC1), mRNA transport (RAE), or mRNA editing (ADAR2, also known as ADARB1). Moreover, we found a high incidence of loss of heterozygosity at chromosome 21q22.3, where the ADAR2 locus is located, in NSCLC cell lines and primary tissues, suggesting that the downregulation of ADAR2 in lung cancer is associated with specific genetic losses. Finally, in a series of adenocarcinoma patients, the expression of five of the deregulated genes (ADAR2, MARS, RAE, SNRPB and SNRPE) correlated with prognosis. Taken together, these results support the hypothesis that changes in RNA metabolism are involved in the pathogenesis of lung cancer, and identify new potential targets for the treatment of this disease.     

突变p53功能研究新进展与个性化的肿瘤治疗新策略

p53是迄今为止研究最多的一种抑癌蛋白,最新研究仍在不断地揭示p53在调控机体代谢、生殖方面的新功能。同时,也揭示了不同p53突变蛋白的获得性新功能在肿瘤发生中的促进作用。这些研究对于了解p53突变的个性化新功能,寻找再激活野生型p53,校正突变p53的新途径奠定了基础,不同突变p53蛋白的个性化治疗将是未来肿瘤治疗的热点。文章综述了已发现的一些突变p53的获得性新功能,及针对不同的p53功能缺陷进行的p53蛋白功能再激活的策略:通过小分子或多肽再激活肿瘤细胞中的p53突变蛋白的野生型功能;通过重组的腺病毒在肿瘤细胞中表达野生型p53蛋白;通过抑制MDM2与p53的相互作用稳定野生型p53蛋白。对p53不同位点突变的深入研究可以帮助我们制定更合理的个性化治疗方案,寻求更有效的肿瘤治疗新途径。     

Endothelin-1 is a novel prognostic factor in non-small cell lung cancer

Endothelin-1 (ET-1) is a potent vasoactive peptide and a hypoxia-inducible angiogenic growth factor associated with the development and growth of solid tumours. This study evaluated the expression of big endothelin-1 (big ET-1), a stable precursor of ET-1, and ET-1 in non-small cell lung cancer (NSCLC). Big ET-1 expression was evaluated in paraffin-embedded tissue sections from 10 NSCLC tumours using immunohistochemistry and in situ hybridisation. The production of big ET-1 and ET-1 was studied in six established NSCLC cell lines. The plasma concentrations of big ET-1 were measured in 30 patients with proven NSCLC prior to chemotherapy by means of a sandwich enzyme-linked immunoassay and compared to levels in 20 normal controls. Big ET-1 immunostaining was detected in the cancer cells of all tumours studied. Using in situ hybridisation, tumour cell big ET-1 mRNA expression was demonstrated in all samples. All six NSCLC cell lines expressed ET-1, with big ET-1 being detected in three. The median big ET-1 plasma level in patients with NSCLC was 5.4 pg/mL (range 0-22.7 pg/mL) and was significantly elevated compared to median big ET-1 plasma levels in controls, 2.1 pg/mL (1.2-13.4 pg/mL) (p = 0.0001). Furthermore, patients with plasma big ET-1 levels above the normal range (upper tertile) had a worse outcome (p = 0.01). In conclusion, big ET-1/ET-1 is expressed by resected NSCLC specimens and tumour cell lines. Plasma big ET-1 levels are elevated in NSCLC patients compared to controls with levels > 7.8 pg/mL being associated with a worse outcome. The development of selective ET-1 antagonists such as Atrasentan indicates that ET-1 may be a therapeutic target in NSCLC.     

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1^−/− tumours in subcutaneous xenograft models, with no significant effect in LIMD1^+/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.Subject terms: Targeted therapies, Non-small-cell lung cancer     

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

Non-small cell lung cancer (NSCLC) still constitutes the most common cancer-related cause of death worldwide. All efforts to introduce suitable treatment options using chemotherapeutics or targeted therapies have, up to this point, failed to exhibit a substantial effect on the 5-year-survival rate. The involvement of epigenetic alterations in the evolution of different cancers has led to the development of epigenetics-based therapies, mainly targeting DNA methyltransferases (DNMTs) and histone-modifying enzymes. So far, their greatest success stories have been registered in hematologic neoplasias. As the effects of epigenetic single agent treatment of solid tumors have been limited, the investigative focus now lies on combination therapies of epigenetically active agents with conventional chemotherapy, immunotherapy, or kinase inhibitors. This review includes a short overview of the most important preclinical approaches as well as an extensive discussion of clinical trials using epigenetic combination therapies in NSCLC, including ongoing trials. Thus, we are providing an overview of what lies ahead in the field of epigenetic combinatory therapies of NSCLC in the coming years.     

Controversies in the management of advanced non-small cell lung cancer: maintenance therapy

The majority of patients with non-small cell lung (NSCLC) present with advanced, metastatic disease at the time of diagnosis. The current state of the art for the management of this condition is first- and second-line chemotherapy (CT), along with appropriate supporting care measures, which are supposed to alleviate symptoms and to improve survival. During the last years, maintenance therapy (MT) was included in the therapeutic algorithm for these patients. MT could be defined as continuation of an active treatment until disease progression in patients who demonstrated a non-progressing status following induction chemotherapy. Despite the results of several randomized trials showing a significant benefit by using this approach, the strategy is far from being universally accepted. The internationally recognized guidelines provide different recommendation when it comes to this topic, while some major drawbacks in the design of the positive clinical trials may have distorted the relevance of the communicated data. This paper aimed to review the most contentious aspects which should be considered while contemplating the use of MT in the daily clinical practice.     

抗-VEGF和抗-EGFR药物在进展期非小细胞肺癌治疗中的应用

化疗对非小细胞肺癌的疗效已到达平台期,研发更为有效、易耐受的治疗策略势在必行.肿瘤生物学分子机制研究孕育了分子靶向治疗.VEGF、EGFR相关信号通路在肿瘤发生、发展中发挥重要作用,是抗肿瘤药物的重要分子靶点.贝伐单抗联合化疗和小分子酪氨酸激酶抑制剂(埃罗替尼和吉非替尼)分别成为非小细胞肺癌的一、二线治疗方案.本文将综述多种抗-VEGF和抗-EGFR新药在进展期非小细胞肺癌治疗中的临床应用.     

榄香烯治疗非小细胞肺癌的作用机制研究进展

榄香烯注射液是从天然中草药姜科植物温郁金中提取获得的萜烯类化合物,其主要生物学活性为降低肿瘤细胞有丝分裂能力,诱导肿瘤细胞凋亡,抑制肿瘤细胞的生长,从而改善NSCLC患者的临床症状,增强患者免疫力.本文主要从杀灭癌细胞、诱导癌细胞凋亡、抑制癌细胞血管形成、增强患者免疫力等几方面综述榄香烯注射液对非小细胞肺癌的作用机制.     

Recent advances in human sweat metabolomics for lung cancer screening

Introduction

Lung cancer is the leading cause of cancer related mortality owing to the advanced stage it is usually detected because the available diagnostic tests are expensive and invasive; therefore, they cannot be used for general screening.

Objectives

To increase robustness of previous biomarker panels—based on metabolites in sweat samples—proposed by the authors, new samples were collected within different intervals (4 months and 2 years), analyzed at different times (2012 and 2014, respectively) by different analysts to discriminate between LC patients and smokers at risk factor.

Methods

Sweat analysis was carried out by LC–MS/MS with minimum sample preparation and the generated analytical data were then integrated to minimize variability in statistical analysis.

Results

Panels with capability to discriminate LC patients from smokers at risk factor were obtained taken into account the variability between both cohorts as a consequence of the different intervals for samples collection, the times at which the analyses were carried out and the influence of the analyst. Two panels of metabolites using the PanelomiX tool allow reducing false negatives (95 % specificity) and false positives (95 % sensitivity). The first panel (96.9 % specificity and 83.8 % sensitivity) is composed by monoglyceride MG(22:2), muconic, suberic and urocanic acids, and a tetrahexose; the second panel (81.2 % specificity and 97.3 % sensitivity) is composed by the monoglyceride MG(22:2), muconic, nonanedioic and urocanic acids, and a tetrahexose.

Conclusion

The study has allowed obtaining a prediction model more robust than that obtained in the previous study from the authors.

     

Five microRNAs in plasma as novel biomarkers for screening of early-stage non-small cell lung cancer

Background

In order to find novel noninvasive biomarkers with high accuracy for the screening of early-stage non-small cell lung cancer (NSCLC), we investigate the predictive power of 5 microRNAs (miR-20a, miR-145, miR-21, miR223 and miR-221) as potential biomarkers in early-stage NSCLC.

Methods

In training set, 25 early-stage NSCLC patients and 25 matched healthy controls are included to assess the miRNA expression profile between early-stage NSCLC patients and healthy controls by real-time RT-PCR. We found that five of these miRNAs (miR-20a, miR-223, miR-21, miR-221 and miR-145) levels in NSCLC patients were significantly dysregulated compared with the healthy groups and thus were selected to validation set. Therefore, a validation experiment was further performed to investigate the potential predictive power of these five miRNAs based on 126 early-stage NSCLC patients, 42 NCPD patients and 60 healthy controls. The receiver operating characteristic (ROC) curves were generated for the five miRNAs.

Results

ROC curve analyses suggested that these five plasma miRNAs could be promising biomarkers for NSCLC, with relatively high AUC values as follows: miR-20a, 0.89 with 95% CI of [0.85-0.93]; miR-223, 0.94 with 95% CI of [0.91-0.96]; miR-21, 0.77 with 95% CI of [0.71-0.83]; miR-155, 0.92 with 95% CI of [0.89-0.96]; miR-145, 0.77 with 95% CI of [0.71-0.83]. Stratified analyses indicated that plasma miR-20a, miR-223, miR-21 and miR-145 showed better predictive value in smokers than in non-smokers, while miR-155 might be more suitable for non-smokers. In addition, all of these five miRNAs could differentiate NSCLC from controls with a higher accuracy in advanced stage and squamous carcinoma subgroups.

Conclusions

In conclusion, our study suggested that five plasma miRNAs (miR-20a, miR-145, miR-21, miR-223 and miR-221) can be used as promising biomarkers in early screening of NSCLC. Nevertheless, further validation and optimizing improvement should be performed on larger sample to confirm our results.     

Erlotinib in the treatment of non-small cell lung cancer

Because erlotinib, an epidermal growth factor receptor tyrosine kinase (EGFRTK) inhibitor, has been shown to be effective and well-tolerated as a second/third-line treatment in the therapy of advanced non-small cell lung cancer (NSCLC), this agent has been recently approved for human NSCLC therapy in the European Union. Although additive and synergistic effects of erlotinib and conventional chemotherapy were demonstrated in the combined regime preclinically, this has yet to be approved in the clinic. Since erlotinib and cytotoxic drugs have different biological targets, they have distinct side effects as well: erlotinib has no toxic effect on the bone marrow, but can cause diarrhea and rash, the latter being thought to be an indicator of the therapeutic efficacy. Several ongoing clinical trials are investigating the potential role of erlotinib in different settings in human NSCLC. This review intends to integrate our current knowledge on the erlotinib treatment in NSCLC.     

Recent patents concerning targeted therapy of apoptosis resistance in pancreatic cancer

Pancreatic cancer is one of the most malignant forms of cancer. Due to numerous defects of the apoptosis machinery this tumor shows a high resistance towards conventional oncological therapies. On the level of the extrinsic pathway, signal transduction is flawed by over-expression of decoy receptors but also by a dysfunctional death inducing signaling complex (DISC). The mitochondrial pathway, normally stimulated by cell stress and toxic agents is impeded by over-expression of anti-apoptotic members of the Bcl 2 protein family and the so-called inhibitor of apoptosis proteins (IAPs). To overcome the dysfunction of the apoptosis pathway, new therapeutics focus on molecular targets within the apoptosis pathway. Recently, many new treatment modalities have been reported like recombinant ligands of the cell death receptors or inhibitors of anti-apoptotic Bcl-2 members. Furthermore, various substances for the direct activation of the caspase cascade were patented and the over-expression of IAPs could be treated by binding inhibitors or using RNA interference techniques. The present review aims at giving an overview on these new treatment modalities.