Delta‐like protein 3 (DLL3) is a ligand of Notch signaling, which mediates cell‐fate decisions and is tumor‐suppressive or oncogenic depending on the cellular context. Previous studies show that DLL3 ...is highly expressed in small cell lung cancer (SCLC) but not in normal lung tissue, suggesting that DLL3 might be associated with neuroendocrine tumorigenesis. However, its role in SCLC remains unclear. To investigate the role of DLL3 in tumorigenesis in SCLC, we performed loss‐of‐function and gain‐of‐function assays using SCLC cell lines. In vitro analysis of cell migration and invasion by transwell assay showed that DLL3 knockdown reduced migration and invasion of SCLC cells, whereas DLL3 overexpression increased these activities. In addition, DLL3 positively regulated SNAI1 expression and knockdown of SNAI1 attenuated the migration and invasion ability of SCLC cells. Moreover, upregulated DLL3 expression induced subcutaneous tumor growth in mouse models. These results indicate that DLL3 promoted tumor growth, migration and invasion in an SCLC model by modulating SNAI1/Snail.
This study performed in vitro and in vivo analyses of the role of delta‐like protein 3 (DLL3) in small cell lung cancer (SCLC) by targeted siRNA silencing in SCLC cell lines, followed by implantation of DLL3‐overexpressing or control SCLC cells into mouse models to assess altered tumorigenesis. Our results showed that DLL3 downregulation attenuated SCLC‐cell proliferation, migration and invasion in a process involving the attenuation of Snail activation. In addition, we found that DLL3 overexpression promoted subcutaneous tumor growth in the mouse models.
Bromodomain and extraterminal domain (BET) inhibitors are broadly active against distinct types of cancer, including nonsmall cell lung cancer (NSCLC). Previous studies have addressed the effect of ...BET‐inhibiting drugs on the expression of oncogenes such as c‐Myc, but DNA damage repair pathways have also been reported to be involved in the efficacy of these drugs. AZD1775, an inhibitor of the G2‐M cell cycle checkpoint kinase WEE1, induces DNA damage by promoting premature mitotic entry. Thus, we hypothesized that BET inhibition would increase AZD1775‐induced cytotoxicity by impairing DNA damage repair. Here, we demonstrate that combined inhibition of BET and WEE1 synergistically suppresses NSCLC growth both in vitro and in vivo. Two BET inhibitors, JQ1 and AZD5153, increased and prolonged AZD1775‐induced DNA double‐strand breaks (DSBs) and concomitantly repressed genes related to nonhomologous end joining (NHEJ), including XRCC4 and SHLD1. Furthermore, pharmaceutical inhibition of BET or knockdown of the BET protein BRD4 markedly diminished NHEJ activity, and the BET‐inhibitor treatment also repressed myelin transcription factor 1 (MYT1) expression and promoted mitotic entry with subsequent mitotic catastrophe when combined with WEE1 inhibition. Our findings reveal that BET proteins, predominantly BRD4, play an essential role in DSB repair through the NHEJ pathway, and further suggest that combined inhibition of BET and WEE1 could serve as a novel therapeutic strategy for NSCLC.
What's new?
A new combination therapy shows promise against non‐small cell lung cancer (NSCLC). Inhibitors of bromodomain and extraterminal domain (BET) proteins act against various cancers, including NSCLC. Here, the authors investigated the combined effect of BET inhibitors with inhibitors of the tyrosine kinase WEE1. Combined inhibition of BET and WEE1 harms NSCLC in two ways. First, it stifles the non‐homologous end joining mechanism of DNA double‐strand break repair. Furthermore, it forces progression of the cell cycle into mitosis, despite the unrepaired DNA damage, leading to apoptosis. This is the first report to show synergistic action between these two types of inhibitors.
Lorlatinib is a potent, brain‐penetrant, third‐generation anaplastic lymphoma kinase (ALK)/ROS proto‐oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) that is active against most known resistance ...mutations. This is an ongoing phase 1/2, multinational study (NCT01970865) investigating the efficacy, safety and pharmacokinetics of lorlatinib in ALK‐rearranged/ROS1‐rearranged advanced non–small cell lung cancer (NSCLC) with or without intracranial (IC) metastases. Because patterns of ALK TKI use in Japan differ from other regions, we present a subgroup analysis of Japanese patients. Patients were enrolled into six expansion (EXP) cohorts based on ALK/ROS1 mutation status and treatment history. The primary endpoint was the objective response rate (ORR) and the IC‐ORR based on independent central review. Secondary endpoints included pharmacokinetic evaluations. At data cutoff, 39 ALK‐rearranged/ROS1‐rearranged Japanese patients were enrolled across the six expansion cohorts; all received lorlatinib 100 mg once daily. Thirty‐one ALK‐rearranged patients previously treated with ≥1 ALK TKI (EXP2 to EXP5) were evaluable for ORR and 15 were evaluable for IC‐ORR. The ORR and the IC‐ORR for Japanese patients in EXP2‐5 were 54.8% (95% confidence interval CI: 36.0‐72.7) and 46.7% (95% CI: 21.3‐73.4), respectively. Among patients who had received prior alectinib only (EXP3B), the ORR was 42.9%; 95% CI: 9.9‐81.6). The most common treatment‐related adverse event (TRAE) was hypercholesterolemia (79.5%). Hypertriglyceridemia was the most common grade 3/4 TRAE (25.6%). Single‐dose and multiple‐dose pharmacokinetic profiles among Japanese patients were similar to those in non–Japanese patients. Lorlatinib showed clinically meaningful responses and IC responses among ALK‐rearranged Japanese patients with NSCLC who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only. Lorlatinib was generally well tolerated.
Lorlatinib showed clinically meaningful responses (54.8%; 95% CI: 36.0‐72.7) and intracranial responses (46.7%; 95% CI: 21.3‐73.4) among ALK‐rearranged Japanese patients with non–small cell lung cancer who received ≥1 prior ALK TKI, including meaningful responses among those receiving prior alectinib only (42.9%; 95% CI: 9.9‐81.6). Lorlatinib was generally well tolerated, with a similar adverse event profile among Japanese patients to that among the overall population.
Osimertinib is a third‐generation epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitor (TKI) that has shown marked antitumor activity in patients with EGFR‐mutated non–small‐cell lung ...cancer (NSCLC). However, these effects are transient and most patients develop resistance. Reversible drug‐tolerant persister (DTP) cells are defined as a small subpopulation of cells with markedly reduced sensitivity and non‐genetic acquired resistance to EGFR‐TKIs. Notch is a transmembrane receptor that plays an important role in tumorigenesis. We previously reported that there is significant crosstalk between the Notch and EGFR pathways in NSCLC. Moreover, the Notch pathway is associated with resistance to previous‐generation EGFR‐TKIs. However, the role of Notch in osimertinib resistance is not fully understood. In this study, we evaluated whether Notch is involved in osimertinib resistance. We show that NOTCH1 and Notch target genes are upregulated in osimertinib DTP cells, and that the addition of a γ‐secretase inhibitor (GSI), a Notch inhibitor, impairs drug‐tolerant persistence in vitro and in vivo. Compared with osimertinib, combined GSI and osimertinib suppress phospho‐ERK partly by enhancing DUSP1 expression. Furthermore, Notch1 and HES1 were upregulated after EGFR‐TKI treatment in half of human EGFR‐mutated NSCLC tumor tissues. These results suggest that the combination of GSI and osimertinib may be a potential therapy for EGFR‐mutated NSCLC.
The Notch pathway is activated in osimertinib drug‐tolerant persister cells and might be targeted for EGFR‐mutated patients in their osimertinib treatment.
Epidermal growth factor receptor (EGFR)‐tyrosine kinase inhibitors (TKIs) elicit potent cell cycle arrest in EGFR‐mutant non–small‐cell lung cancer (NSCLC) cells. However, little is known about the ...mechanisms through which these drugs alter the tumor phenotype that contributes to the immune escape of EGFR‐mutant cells. Using EGFR‐mutant NSCLC cell lines and tissue samples from patients, we investigated the changes in immune checkpoints expressed in tumor cells following EGFR inhibition. Subsequently, we also analyzed the role of soluble factors from the dying tumor cells in the activation of immune signaling pathways involved in therapy resistance. Upon EGFR‐TKI treatment, we found that EGFR‐mutant cells upregulated the expression of innate immune checkpoint CD24 in vitro. We then analyzed biopsy samples from six patients who developed resistance to a first‐generation EGFR‐TKI without the acquired T790M mutation. Immunohistochemistry revealed that levels of tumor CD24 expression were increased upon treatment compared with those from pre‐treatment samples. Monocyte‐derived macrophages facilitated antibody‐dependent cellular phagocytosis when EGFR‐TKI‐treated EGFR‐mutant cells were incubated with anti‐CD24 antibodies in vitro, suggesting that CD24 may be a therapeutical target for EGFR‐mutant lung cancer. Moreover, EGFR inhibition accelerated the release of cell‐free DNA (cfDNA) from dying tumor cells, which activated the type I interferon signaling pathways in human THP‐1 monocytes in a stimulator of interferon genes‐dependent manner. Our study indicates that EGFR inhibition in EGFR‐mutant NSCLC cells fosters a tumor microenvironment associated with immune escape. Thus, CD24 targeted therapy and cfDNA monitoring may contribute to improved treatment outcomes in patients with EGFR‐mutant NSCLC.
EGFR inhibition in EGFR‐mutant lung cancer cells results in the upregulation of tumor CD24. It also accelerates the release of tumor‐derived cell‐free DNA, triggering the type I interferon pathways. These biomarkers are potential targets to overcome the resistance to EGFR‐targeted therapy.
Recent discoveries have revealed that human cancer involves aberrant epigenetic alterations. We and others have previously shown that the histone methyltransferase EZH2, the catalytic subunit of ...polycomb repressive complex 2 (PRC2), is frequently overexpressed in non‐small‐cell lung cancer (NSCLC) and that an EZH2 inhibitor, 3‐deazaneplanocin A, inhibits the proliferation of NSCLC cells. Transcriptional silencing by EZH2 was recently shown to be required for the activity of histone deacetylases (HDACs) that interact with another PRC2 protein, EED. To develop a more effective epigenetic therapy for NSCLC, we determined the effects of co‐treatment with 3‐deazaneplanocin A and the HDAC inhibitor vorinostat (SAHA) in NSCLC cells. The co‐treatment synergistically suppressed the proliferation of all tested NSCLC cell lines, regardless of their epidermal growth factor receptor (EGFR) status. The synergistic effect was associated with slightly decreased histone H3 lysine 27 trimethylation, modestly increased histone acetylation, and the depletion of EZH2 and other PRC2 proteins. The co‐treatment resulted in an accumulation of p27Kip1, decrease in cyclin A, and increased apoptotic fraction in an additive/synergistic manner. Interestingly, the co‐treatment strongly suppressed EGFR signaling, not only in EGFR‐wild‐type NSCLC cells, but also in EGFR‐mutant cells, mainly through dephosphorylation of EGFR. Furthermore, the co‐treatment suppressed the in vivo tumor growth of EGFR‐mutant, EGFR–tyrosine kinase‐resistant H1975 cells more effectively than did each agent alone, without visible toxicity. These results suggest that the combined pharmacological targeting of EZH2 and HDACs may provide more effective epigenetic therapeutics for NSCLC.
The present study clearly demonstrated that the combined therapy with inhibitors of the histone methylase EZH2 and the histone de acetylases HDACs had a synergistic growth suppressive effect and induced substantial apoptosis in NSCLC cells. Interestingly, the co‐treatment suppressed the in vivo tumor growth of EGFR‐mutant, EGFR‐TKI‐resistant H1975 cells more effectively than single treatment via inhibition of the EGFR signaling pathway, suggesting that the combined pharmacological targeting of the histone modification enzymes may provide more effective epigenetic therapeutics for NSCLC including that with EGFR‐TKI‐resistant mutations.
Background and Aim
Immune checkpoint inhibitors (ICI) have revolutionized anti‐malignancy therapy and thus have been increasingly used. Although ICI may cause immune‐related adverse events (irAE) in ...various organs, including the liver, the prevalence and predictive factors of irAE have not been clarified.
Methods
In this retrospective study, consecutive patients who had malignancies and were treated with ICI without other chemotherapeutic agents at Hokkaido University Hospital between 2014 and 2019 were screened. Patients were excluded if they were < 20 years old and had insufficient clinical data.
Results
Of the 233 patients screened, 202 patients met the inclusion criteria and were included in the analysis. The patients were aged 25–92 years, and 60.9% were male. The patients received nivolumab (n = 137), pembrolizumab (n = 45), ipilimumab (n = 17), atezolizumab (n = 2), and avelumab (n = 1). The prevalence of any grade and grade ≥ 3 irAE hepatitis was 8.4% (17/202) and 4.0% (8/202), respectively. irAE hepatitis occurred at a median duration of 42 days in any grade and 36 days in grade ≥ 3 after ICI initiation. The clinical course of grade ≥ 3 irAE hepatitis was generally favorable; however, 50% required corticosteroid treatment and two patients required additional mycophenolate mofetil. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.
Conclusions
Grade ≥ 3 irAE hepatitis was observed in 4.0% of the patients who were treated with ICI. Female sex and history of ICI treatment were significantly associated with the incidence of grade ≥ 3 irAE hepatitis.
Drop finger caused by lung cancer metastasis Sumi, Toshiyuki; Sakakibara‐Konishi, Jun; Suzuki, Keito ...
Respirology case reports,
January 2024, Volume:
12, Issue:
1
Journal Article
Peer reviewed
Open access
Skeletal muscle metastasis of lung cancer is rare. However, clinicians should be aware that tumour‐induced nerve compression symptoms may develop.
We present a rare case of posterior interosseous ...nerve (PIN) palsy secondary to lung cancer metastasis.
Background
Delta‐like protein 3 (DLL3) is a Notch ligand that has an important role in the tumorigenesis of small cell lung cancer (SCLC). Recently, rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted ...antibody‐drug conjugate, has been developed for treating SCLC. DLL3 is a transcriptional target of the achaete‐scute homolog‐1 (ASCL1) transcription factor, which is involved in pulmonary neuroendocrine cell development. However, the relationship between DLL3 and/or ASCL1 expression and the clinical features of SCLC remains unknown, especially for early‐stage resected SCLC. This study aimed to investigate the expression of DLL3 and ASCL1 in resected SCLC samples using immunohistochemical analysis.
Materials and Methods
We collected 95 surgically resected SCLC samples, which were formalin fixed and paraffin embedded. Immunohistochemistry staining was performed to investigate the correlation between the expression of either DLL3 or ASCL1 and clinicopathological features of study patients.
Results
Seventy‐seven (83%) of 93 immunohistochemically evaluable samples were positive for DLL3 (expression in ≥1% of tumor cells), and DLL3‐high expression (≥75%) was observed in 44 samples (47%). Sixty‐one (64%) of 95 samples were positive for ASCL1 (expression in ≥5% of tumor cells). A positive correlation was observed between DLL3 and ASCL1 expression. DLL3 and ASCL1 expression were not associated with survival in SCLC patients. DLL3 was more prevalent in patients with advanced clinical disease.
Conclusion
DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of SCLC.
Implications for Practice
This article examines the relationship between delta‐like protein 3 (DLL3) and achaete‐scute homolog‐1 (ASCL1) protein expression with the clinical features of 95 surgically resected small cell lung cancer (SCLC). DLL3 is attracting attention because rovalpituzumab tesirine (Rova‐T), a DLL3‐targeted antibody‐drug conjugate, was developed recently. DLL3 and ASCL1 were highly expressed in patients with surgically resected SCLC. DLL3 and ASCL1 may be targets for the treatment of early‐stage SCLC, including with Rova‐T.
摘要
背景。 δ 样蛋白 3 (DLL3) 是一种 Notch 配体，在小细胞肺癌 (SCLC) 的发生中起着重要作用。近年针对 SCLC 治疗，研制出了一种叫作 rovalpituzumab tesirine (Rova‐T) 的药物，是一种 DLL3 靶向抗体‐药物偶联物。DLL3 是 achaet ‐scute 同源物‐1 (ASCL1) 转录因子的转录靶点，参与肺神经内分泌细胞发育。然而，目前尚不明确 DLL3 和/或 ASCL1 表达与 SCLC 的临床特征之间的关系，尤其是对于早期可切除的 SCLC 患者。本项研究旨在通过免疫组织化学分析方法，研究 DLL3 和 ASCL1 在切除的 SCLC 样本中的表达。
材料和方法。研究选择了 95 例手术切除的 SCLC 标本，标本为福尔马林固定石蜡包埋组织。采用免疫组织化学染色，探讨研究患者的 DLL3 或 ASCL1 表达与临床病理特征的关系。
结果。93 例免疫组化评价标本中，77 例 (83%) 呈 DLL3 阳性(肿瘤细胞表达 ≥1%)，44 例(47%) 呈 DLL3 高表达 (≥75%)。95 个标本中有 61 个 (64%) 呈 ASCL1 阳性(肿瘤细胞表达 ≥5%)。DLL3 与 ASCL1 表达呈正相关。DLL3 和 ASCL1 的表达与 SCLC 患者的生存无关。DLL3 在晚期临床疾病患者中更为常见。
结论。DLL3 和 ASCL1 在手术可切除的 SCLC 患者中高表达。DLL3 和 ASCL1 可能是治疗 SCLC 的靶点。
实践意义:本文结合 95 例手术可切除性小细胞肺癌 (SCLC) 的临床特点，探讨了 δ 样蛋白 3 (DLL3) 与 achaet ‐scute 同源物‐1 (ASCL1) 表达的关系。DLL3 因新研制的一种 DLL3 靶向抗体‐药物偶联物 rovalpituzumab tesirine (Rova‐T) 而备受关注。DLL3 和 ASCL1 在手术可切除的 SCLC 患者中高表达。DLL3 和 ASCL1 可能是治疗早期 SCLC 的靶点，包括 Rova‐T。
Growing evidence suggests that DLL3 has a role in the tumorigenesis of small‐cell lung cancer. This article reports on the relationship between DLL3 and ASCL1 expression in resected small‐cell lung cancer samples using immunohistochemical analysis.
Although carboplatin (CBDCA) is classified as a moderately emetogenic agent, the majority of guidelines recommend the use of a neurokinin-1 receptor antagonist in addition to a 5-hydroxytryptamine ...type 3 receptor antagonist with dexamethasone (DEX) for CBDCA-containing chemotherapy because of its higher emetogenic risk. However, the additional efficacy of aprepitant (APR) in CBDCA-containing treatment remains controversial, and data on multiple-day treatments are limited. Etoposide (ETP) was administered on days 1–3 in the CBDCA + ETP regimen, and it is important to evaluate suitable antiemetic therapy for the regimen. Therefore, we evaluated the efficacy of additional APR in CBDCA + ETP. Patients were divided into two groups and retrospectively evaluated. One was the control group, which was prophylactically administered palonosetron (PALO) and DEX, and the other was the APR group, which received APR orally with PALO and DEX. The primary endpoint was complete response (CR) between the groups. The overall CR rates were 75.0 and 76.4% in the control and APR groups, respectively, with no significant difference (p = 1.00). In the acute phase, it was 88.9 and 97.2%, respectively, and 86.1 and 79.2% in the delayed phase, respectively, without significant differences (p = 0.10 and 0.38, respectively). The incidence and severity of nausea, vomiting, and anorexia were not significantly different between the two groups in the acute and delayed phases. Our findings suggest that combining APR with PALO and DEX does not improve the CR rate in CBDCA + ETP therapy.
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