Lung neoplasms are the leading cause of death by cancer worldwide. Non-small cell lung cancer (NSCLC) constitutes more than 80% of all lung malignancies and the majority of patients present advanced ...disease at onset. However, in the last decade, multiple oncogenic driver alterations have been discovered and each of them represents a potential therapeutic target. Although KRAS mutations are the most frequently oncogene aberrations in lung adenocarcinoma patients, effective therapies targeting KRAS have yet to be developed. Moreover, the role of KRAS oncogene in NSCLC remains unclear and its predictive and prognostic impact remains controversial. The study of the underlying biology of KRAS in NSCLC patients could help to determine potential candidates to evaluate novel targeted agents and combinations that may allow a tailored treatment for these patients. The aim of this review is to update the current knowledge about KRAS-mutated lung adenocarcinoma, including a historical overview, the biology of the molecular pathways involved, the clinical relevance of KRAS mutations as a prognostic and predictive marker and the potential therapeutic approaches for a personalized treatment of KRAS-mutated NSCLC patients.
Cellular starvation is typically a consequence of tissue injury that disrupts the local blood supply but can also occur where cell populations outgrow the local vasculature, as observed in solid ...tumors. Cells react to nutrient deprivation by adapting their metabolism, or, if starvation is prolonged, it can result in cell death. Cell starvation also triggers adaptive responses, like angiogenesis, that promote tissue reorganization and repair, but other adaptive responses and their mediators are still poorly characterized. To explore this issue, we analyzed secretomes from glucose-deprived cells, which revealed up-regulation of multiple cytokines and chemokines, including IL-6 and IL-8, in response to starvation stress. Starvation-induced cytokines were cell type-dependent, and they were also released from primary epithelial cells. Most cytokines were up-regulated in a manner dependent on NF-κB and the transcription factor of the integrated stress response ATF4,which bound directly to the IL-8 promoter. Furthermore, glutamine deprivation, as well as the antimetabolic drugs 2-deoxyglucose and metformin, also promoted the release of IL-6 and IL-8. Finally, some of the factors released from starved cells induced chemotaxis of B cells, macrophages, and neutrophils, suggesting that nutrient deprivation in the tumor environment can serve as an initiator of tumor inflammation.
Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted ...therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.
The aim of this study was to identify differentially-expressed miRNAs in the serum of non-small cell lung cancer (NSCLC) patients that might be a clinically-useful tool for lung cancer early ...detection. We performed miRNA expression profile analysis using TaqMan OpenArray Human panel in a discovery set of 70 serum samples obtained at lung tumor resection and 22 non-cancer subjects (NC). Selected serum miRNAs were then validated by quantitative PCR using an independent validation set of serum samples from LC patients (n = 84) and NC (n = 23). Sixty miRNAs were significantly up-regulated and 31 were down-regulated in the serum from NSCLC patients versus NC (adjusted p < 0.001). Four miRNAs (miR-193b, miR-301, miR-141 and miR-200b) were selected for validating their diagnostic value in an independent cohort. In the discovery set, the ROC plot derived from the combination of these miRNAs yielded an area under the curve (AUC) of 0.985 (95% CI 0.961-1.000, p < 0.001). In the test set, this miRNA signature exhibited an AUC of 0.993 (95% CI 0.979-1.000, p < 0.001). In conclusion, we identified a serum 4-miRNA signature that discriminated with high accuracy lung cancer patients from NC. Further prospective validation of this miRNA signature is warranted.
Abstract
Resistance to targeted cancer drugs is thought to result from selective pressure exerted by a high drug dose. Partial inhibition of multiple components in the same oncogenic signalling ...pathway may add up to complete pathway inhibition, while decreasing the selective pressure on each component to acquire a resistance mutation. We report here testing of this Multiple Low Dose (MLD) therapy model in
EGFR
mutant NSCLC. We show that as little as 20% of the individual effective drug doses is sufficient to completely block MAPK signalling and proliferation when used in 3D (RAF + MEK + ERK) or 4D (EGFR + RAF + MEK + ERK) inhibitor combinations. Importantly,
EGFR
mutant NSCLC cells treated with MLD therapy do not develop resistance. Using several animal models, we find durable responses to MLD therapy without associated toxicity. Our data support the notion that MLD therapy could deliver clinical benefit, even for those having acquired resistance to third generation EGFR inhibitor therapy.
To determine whether different subtypes of lung adenocarcinoma (AC) have distinct microRNA (miRNA) expression profiles, and to identify miRNAs associated with aggressive subgroups of resected lung ...AC.
miRNA expression profile analysis was performed in 91 resected lung AC and 10 matched nonmalignant lung tissues using a PCR-based array. An independent cohort of 60 lung ACs was used for validating by quantitative PCR the top 3 prognostic miRNAs. Gene-expression data from 51 miRNA profiled tumors was used for determining transcript-specific miRNA correlations and gene-enrichment pathway analysis.
Unsupervised hierarchical clustering of 356 miRNAs identified 3 major clusters of lung AC correlated with stage (P = 0.023), tumor differentiation (P < 0.003), and IASLC histologic subtype of lung AC (P < 0.005). Patients classified in cluster 3 had worse survival as compared with the other clusters. Eleven of 22 miRNAs associated with poor survival were encoded in a large miRNA cluster at 14q32. The top 3 prognostic 14q32 miRNAs (miR-411, miR-370, and miR-376a) were validated in an independent cohort of 60 lung AC. A significant association with cell migration and cell adhesion was found by integrating gene-expression data with miR-411, miR-370, and miR-376a expression. miR-411 knockdown significantly reduced cell migration in lung AC cell lines and this miRNA was overexpressed in tumors from patients who relapsed systemically.
Different morphologic subtypes of lung AC have distinct miRNA expression profiles, and 3 miRNAs encoded at 14q32 (miR-411, miR-370, and miR-376a) were associated with poor survival after lung AC resection.
Dual blockade of the EGFR and VEGF pathways in EGFR-mutated metastatic non-small-cell lung cancer (NSCLC) is supported by preclinical and clinical data, yet the approach is not widely implemented. ...RELAY assessed erlotinib, an EGFR tyrosine kinase inhibitor (TKI) standard of care, plus ramucirumab, a human IgG1 VEGFR2 antagonist, or placebo in patients with untreated EGFR-mutated metastatic NSCLC.
This is a worldwide, double-blind, phase 3 trial done in 100 hospitals, clinics, and medical centres in 13 countries. Eligible patients were aged 18 years or older (20 years or older in Japan and Taiwan) at the time of study entry, had stage IV NSCLC, with an EGFR exon 19 deletion (ex19del) or exon 21 substitution (Leu858Arg) mutation, an Eastern Cooperative Oncology Group performance status of 0 or 1, and no CNS metastases. We randomly assigned eligible patients in a 1:1 ratio to receive oral erlotinib (150 mg/day) plus either intravenous ramucirumab (10 mg/kg) or matching placebo once every 2 weeks. Randomisation was done by an interactive web response system with a computer-generated sequence and stratified by sex, geographical region, EGFR mutation type, and EGFR testing method. The primary endpoint was investigator-assessed progression-free survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This trial is registered at ClinicalTrials.gov, NCT02411448, and is ongoing for long-term survival follow-up.
Between Jan 28, 2016, and Feb 1, 2018, 449 eligible patients were enrolled and randomly assigned to treatment with ramucirumab plus erlotinib (n=224) or placebo plus erlotinib (n=225). Median duration of follow-up was 20·7 months (IQR 15·8–27·2). At the time of primary analysis, progression-free survival was significantly longer in the ramucirumab plus erlotinib group (19·4 months 95% CI 15·4–21·6) than in the placebo plus erlotinib group (12·4 months 11·0–13·5), with a stratified hazard ratio of 0·59 (95% CI 0·46–0·76; p<0·0001). Grade 3–4 treatment-emergent adverse events were reported in 159 (72%) of 221 patients in the ramucirumab plus erlotinib group versus 121 (54%) of 225 in the placebo plus erlotinib group. The most common grade 3–4 treatment-emergent adverse events in the ramucirumab plus erlotinib group were hypertension (52 24%; grade 3 only) and dermatitis acneiform (33 15%), and in the placebo plus erlotinib group were dermatitis acneiform (20 9%) and increased alanine aminotransferase (17 8%). Treatment-emergent serious adverse events were reported in 65 (29%) of 221 patients in the ramucirumab plus erlotinib group and 47 (21%) of 225 in the placebo plus erlotinib group. The most common serious adverse events of any grade in the ramucirumab plus erlotinib group were pneumonia (seven 3%) and cellulitis and pneumothorax (four 2%, each); the most common in the placebo plus erlotinib group were pyrexia (four 2%) and pneumothorax (three 1%). One on-study treatment-related death due to an adverse event occurred (haemothorax after a thoracic drainage procedure for a pleural empyema) in the ramucirumab plus erlotinib group.
Ramucirumab plus erlotinib demonstrated superior progression-free survival compared with placebo plus erlotinib in patients with untreated EGFR-mutated metastatic NSCLC. Safety was consistent with the safety profiles of the individual compounds in advanced lung cancer. The RELAY regimen is a viable new treatment option for the initial treatment of EGFR-mutated metastatic NSCLC.
Eli Lilly.
Lung cancer is emerging as a paradigm for disease molecular subtyping, facilitating targeted therapy based on driving somatic alterations. Here we perform transcriptome analysis of 153 samples ...representing lung adenocarcinomas, squamous cell carcinomas, large cell lung cancer, adenoid cystic carcinomas and cell lines. By integrating our data with The Cancer Genome Atlas and published sources, we analyse 753 lung cancer samples for gene fusions and other transcriptomic alterations. We show that higher numbers of gene fusions is an independent prognostic factor for poor survival in lung cancer. Our analysis confirms the recently reported CD74-NRG1 fusion and suggests that NRG1, NF1 and Hippo pathway fusions may play important roles in tumours without known driver mutations. In addition, we observe exon-skipping events in c-MET, which are attributable to splice site mutations. These classes of genetic aberrations may play a significant role in the genesis of lung cancers lacking known driver mutations.
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