ALK, ROS1, and RET kinase fusions are important predictive biomarkers of tyrosine kinase inhibitors (TKIs) in non‐small‐cell lung cancer (NSCLC). Analysis of cell‐free DNA (cfDNA) provides a ...noninvasive method to identify gene changes in tumor cells. The present study sought to use cfRNA and cfDNA for identifying fusion genes. A reliable protocol was established to detect fusion genes using cfRNA and assessed the analytical validity and clinical usefulness in 30 samples from 20 cases of fusion‐positive NSCLC. The results of cfRNA‐based assays were compared with tissue biopsy and cfDNA‐based liquid biopsy (Guardant360 plasma next‐generation sequencing NGS assay). The overall sensitivity of the cfRNA‐based assay was 26.7% (8/30) and that of cfDNA‐based assay was 16.7% (3/18). When analysis was limited to the samples collected at chemo‐naïve or progressive disease status and available for both assays, the sensitivity of the cfRNA‐based assay was 77.8% (7/9) and that of cfDNA‐based assay was 33.3% (3/9). Fusion gene identification in cfRNA was correlated with treatment response. These results suggest that the proposed cfRNA assay is a useful diagnostic test for patients with insufficient tissues to facilitate effective administration of first‐line treatment and is a useful tool to monitor the progression of NSCLC for consideration of second‐line treatments.
cfRNA‐ and cfDNA‐based assays are evaluated in 20 cases of fusion‐positive NSCLC. cfRNA assay was superior to cfDNA assay for the detection of gene fusions. The results of the cfRNA assay were consistent with the therapeutic effect.
The discovery of oncogenic driver gene mutations, including epidermal growth factor receptor (EGFR) mutation, anaplastic lymphoma kinase (ALK) fusion, ROS proto-oncogene 1 (ROS1) fusion, and ret ...proto-oncogene (RET) fusion, has led to the development of molecularly targeted therapy for non-small-cell lung cancer (NSCLC). This therapy has changed the standard of care for NSCLC. Despite the dramatic response to molecularly targeted therapy, almost all patients ultimately develop resistance to the drugs. To understand the mechanisms of resistance to molecularly targeted agents, it is essential to understand the molecular pathways of NSCLC. Here, we review the mechanisms of resistance to molecularly targeted therapy and discuss strategies to overcome drug resistance.
Among all types of cancer, incidence of lung cancer remains the highest with regard to cancer-related mortality. Problems contributing to recurrence of the disease include metastasis and drug ...resistance. Mounting evidence has demonstrated involvement of epithelial mesenchymal transition (EMT) in cancer progression. EMT is a critical mechanism ensuring tissue remodeling during morphogenesis of multicellular organisms. Therefore, understanding of the biology of this process for identification of potential EMT-targeted therapeutic strategies for the benefit cancer patients is necessary. This review describes recent evidence of EMT involvement in drug resistance and metastasis of cancers, with an emphasis on lung cancer.
Nausea and diarrhea are the most common adverse effects of nintedanib in patients with idiopathic pulmonary fibrosis (IPF). However, the clinical risk factors for these side effects remain unknown. ...In the present study, we investigated the characteristics of patients who developed gastrointestinal side effects during nintedanib treatment for IPF and determined the risk factors for these side effects. We enrolled 77 patients with IPF who received nintedanib between October 2015 and March 2018. Performance status (PS) as a patient's general condition, body mass index (BMI), modified Medical Research Council Dyspnea Scale score, severity of IPF at nintedanib initiation, and gastrointestinal toxicity of nintedanib were evaluated. In total, 25 and 27 patients exhibited nausea and diarrhea, respectively, during the follow-up period. A poor PS, low BMI, and full dosage of nintedanib at treatment initiation were risk factors for nausea. A low BMI was a significant risk factor for diarrhea, which could be prevented by combination treatment with nintedanib and prednisolone. In addition, the mean annual rate of decline in forced vital capacity was significantly greater in patients with nausea than in patients without nausea. In conclusion, our findings suggest that patients with a low BMI and/or poor PS and those who receive the full nintedanib dosage at treatment initiation are more susceptible to gastrointestinal adverse effects during nintedanib treatment. Addition of prednisolone to the treatment regimen may prevent the development of diarrhea during treatment.
Accumulating evidence implicates heterogeneity within cancer cell populations in the response to stressful exposures, including drug treatments. While modeling the acute response to various ...anticancer agents in drug-sensitive human tumor cell lines, we consistently detected a small subpopulation of reversibly “drug-tolerant” cells. These cells demonstrate >100-fold reduced drug sensitivity and maintain viability via engagement of IGF-1 receptor signaling and an altered chromatin state that requires the histone demethylase RBP2/KDM5A/Jarid1A. This drug-tolerant phenotype is transiently acquired and relinquished at low frequency by individual cells within the population, implicating the dynamic regulation of phenotypic heterogeneity in drug tolerance. The drug-tolerant subpopulation can be selectively ablated by treatment with IGF-1 receptor inhibitors or chromatin-modifying agents, potentially yielding a therapeutic opportunity. Together, these findings suggest that cancer cell populations employ a dynamic survival strategy in which individual cells transiently assume a reversibly drug-tolerant state to protect the population from eradication by potentially lethal exposures.
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► Human cancer cell lines harbor a subpopulation of “drug-tolerant” cells ► The drug-tolerant state can emerge de novo and is transiently maintained ► The emergence of drug tolerance requires IGF-1R signaling ► Drug tolerance involves distinct chromatin states that can be disrupted
Invasive mucinous adenocarcinoma (IMA) of the lung is a unique variant of lung adenocarcinoma. Aberrant mucin expression is associated with cancer development and metastasis. However, the ...clinicopathological significance of mucin expression in IMA is not fully understood. Herein, we evaluated the clinicopathological, immunohistochemical, and molecular characteristics of 70 IMA tumors. EGFR, KRAS, GNAS, and TP53 mutations were assessed by PCR-based sequencing. Next-generation sequencing was used to assess cases without EGFR/KRAS mutations. A NanoString-based screening for fusions was performed in all IMAs without mitogenic driver mutations. Expression of mucins (MUC1, MUC2, MUC4, MUC5AC, and MUC6) was evaluated by immunohistochemistry and categorized as follows: negative (<10% of tumor cells), patchy expression (<90% of tumor cells), or diffuse expression (≥90% of tumor cells). Immunohistochemical testing for transcription factors (TTF-1, CDX2, HNF1β, HNF3α, HNF3β, and HNF4α) was also performed. As expected, KRAS mutations were the most common (in 67% of cases), followed by small numbers of other alterations. Patchy or diffuse expression of MUC1, MUC2, MUC4, MUC5AC, and MUC6 was observed in 52% or 6%, 3% or 0%, 30% or 3%, 26% or 73%, and 59% or 27% of cases, respectively. Furthermore, all IMAs were generally positive for HNF1β (100%), HNF3α (100%), HNF3β (100%), and HNF4α (99%) but were positive less often for TTF-1 (6%) and CDX2 (9%). Overall, there was no significant correlation between mucin expression and transcription factor expression. Unexpectedly, diffuse expression of MUC6 was significantly associated with KRAS-wild-type tumors (p = 0.0008), smaller tumor size (p = 0.0073), and tumors in female patients (p = 0.0359) in multivariate analyses. Furthermore, patients with tumors exhibiting diffuse MUC6 expression had significantly favorable outcomes. Notably, none of these patients died of the disease. Our data suggested that diffuse expression of MUC6 defines a distinct clinicopathological subset of IMA characterized by wild-type KRAS and possibly less aggressive clinical course.
We previously reported the role of IL-6 in a murine model of cancer cachexia and currently documented a patient in whom tocilizumab, anti-IL-6 receptor antibody, dramatically improved cachexia ...induced by IL-6 over-expressing lung cancer. Despite this potential to alleviate cancer cachexia, tocilizumab has not been approved for this clinical use. Therefore, preceding our planned clinical trial of tocilizumab, we designed the two studies described here to evaluate the levels of IL-6 in patients with lung cancer and the effect of tocilizumab in a murine model of human cancer cachexia.
First, we measured serum IL-6 levels in patients with lung cancer and analyzed its association with cachexia and survival. Next, we examined the effect of a rodent analog of tocilizumab (MR16-1) in the experimental cachexia model.
Serum IL-6 levels were higher in patients with cachexia than those without cachexia. In patients with chemotherapy-resistant lung cancer, a high IL-6 serum level correlated strongly with survival, and the cut-off level for affecting their prognosis was 21 pg/mL. Meanwhile, transplantation of IL-6-expressing Lewis Lung Carcinoma cells caused cachexia in mice, which then received either MR16-1 or 0.9% saline. Tumor growth was similar in both groups; however, the MR16-1 group lost less weight, maintained better food and water intake and had milder cachectic features in blood. MR16-1 also prolonged the survival of LLC-IL6 transplanted mice (36.6 vs. 28.5 days, p = 0.016).
Our clinical and experimental studies revealed that serum IL-6 is a surrogate marker for evaluating cachexia and the prognosis of patients with chemotherapy resistant metastatic lung cancer and that tocilizumab has the potential of improving prognosis and ameliorating the cachexia that so devastates their quality of life. This outcome greatly encourages our clinical trials to evaluate the safety and efficacy of tocilizumab treatment for patients with increased serum IL-6.
Background: Although direct oral anticoagulants (DOACs) are widely used in Japanese patients with atrial fibrillation (AF), large-scale investigations into their use, with suitable follow-up times ...and rates, are lacking. Methods and Results: The SAKURA AF Registry is a prospective multicenter registry created to investigate therapeutic outcomes of oral anticoagulant (OAC) use in Japanese AF patients. We conducted a study involving 3,237 enrollees from 63 institutions in the Tokyo area being treated with any of 4 DOACs (n=1,676) or warfarin (n=1,561) and followed-up for a median of 39.3 months (range 28.5–43.6 months). Analyses of 1- and 2-year follow-up data available for 3,157 (97.5%) and 2,952 (91.2%) patients, respectively, showed no significant differences in rates of stroke or systemic embolism (SE), major bleeding, and all-cause mortality for DOAC vs. warfarin users (1.2 vs. 1.8%/year, 0.5 vs. 1.2%/year, and 2.1 vs. 1.7%/year, respectively). Under propensity score matching, the incidence of stroke or SE (P=0.679) and all-cause death (P=0.864) remained equivalent, but the incidence of major bleeding was significantly lower (P=0.014) among DOAC than warfarin users. Conclusions: A high follow-up rate allowed us to obtain reliable data on the status of OAC use and therapeutic outcomes among AF patients in Japan. Warfarin and DOACs appear to yield equivalent 3-year stroke and all-cause mortality rates, but DOACs appear to reduce the risk of major bleeding.
Neointimal lesion and medial wall thickness of pulmonary arteries (PAs) are common pathological findings in pulmonary arterial hypertension (PAH). Platelet-derived growth factor (PDGF) and fibroblast ...growth factor (FGF) signaling contribute to intimal and medial vascular remodeling in PAH. Nintedanib is a tyrosine kinase inhibitor whose targets include PDGF and FGF receptors. Although the beneficial effects of nintedanib were demonstrated for human idiopathic pulmonary fibrosis, its efficacy for PAH is still unclear. Thus, we hypothesized that nintedanib is a novel treatment for PAH to inhibit the progression of vascular remodeling in PAs. We evaluated the inhibitory effects of nintedanib both in endothelial mesenchymal transition (EndMT)-induced human pulmonary microvascular endothelial cells (HPMVECs) and human pulmonary arterial smooth muscle cells (HPASMCs) stimulated by growth factors. We also tested the effect of chronic nintedanib administration on a PAH rat model induced by Sugen5416 (a VEGF receptor inhibitor) combined with chronic hypoxia. Nintedanib was administered from weeks 3 to 5 after Sugen5416 injection, and we evaluated pulmonary hemodynamics and PAs pathology. Nintedanib attenuated the expression of mesenchymal markers in EndMT-induced HPMVECs and HPASMCs proliferation. Phosphorylation of PDGF and FGF receptors was augmented in both intimal and medial lesions of PAs. Nintedanib blocked these phosphorylation, improved hemodynamics and reduced vascular remodeling involving neointimal lesions and medial wall thickening in PAs. Additionally, expressions Twist1, transcription factors associated with EndMT, in lung tissue was significantly reduced by nintedanib. These results suggest that nintedanib may be a novel treatment for PAH with anti-vascular remodeling effects.
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