scholarly journals EML4-ALK V3 drives cell migration through NEK9 and NEK7 kinases in non-small-cell lung cancer

2019 ◽  
Author(s):  
Laura O’Regan ◽  
Giancarlo Barone ◽  
Rozita Adib ◽  
Chang Gok Woo ◽  
Hui Jeong Jeong ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Disease Progression ◽  
Therapeutic Response ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Constitutive Activation ◽  
Microtubule Stabilization ◽  
Lung Adenocarcinomas

ABSTRACTEML4-ALK is an oncogenic fusion present in ∼5% lung adenocarcinomas. However, distinct EML4-ALK variants differ in the length of the EML4 microtubule-associated protein encoded within the fusion and are associated with a poorly understood variability in disease progression and therapeutic response. Here, we show that EML4-ALK variant 3, which is linked to accelerated metastatic spread and worse patient outcome, causes microtubule stabilization, formation of extended cytoplasmic protrusions, loss of cell polarity and increased cell migration. Strikingly, this is dependent upon the NEK9 kinase that interacts with the N-terminal region of EML4. Overexpression of wild-type EML4, as well as constitutive activation of NEK9, also perturbs cell morphology and accelerates cell migration in a manner that requires the downstream kinase NEK7 but not ALK activity. Moreover, elevated NEK9 is associated in patients with EML4-ALK V3 expression, as well as reduced progression-free and overall survival. Hence, we propose that EML4-ALK V3 promotes microtubule stabilization through recruitment of NEK9 and NEK7 to increase cell migration and that this represents a novel actionable pathway that drives disease progression in lung cancer.

scholarly journals Randomized Phase III Study of Continuation Maintenance Bevacizumab With or Without Pemetrexed in Advanced Nonsquamous Non–Small-Cell Lung Cancer: COMPASS (WJOG5610L)

2020 ◽  
Vol 38 (8) ◽  
pp. 793-803
Author(s):  
Takashi Seto ◽  
Koichi Azuma ◽  
Takeharu Yamanaka ◽  
Shunichi Sugawara ◽  
Hiroshige Yoshioka ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Maintenance Therapy ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Induction Therapy ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung ◽  
Continuation Maintenance

PURPOSE Patients with non–small-cell lung cancer (NSCLC) have been shown to benefit from maintenance therapy. COMPASS evaluated the efficacy and safety of bevacizumab with or without pemetrexed as continuation maintenance therapy after carboplatin, pemetrexed, and bevacizumab induction therapy. PATIENTS AND METHODS Patients with untreated advanced nonsquamous NSCLC without confirmed EGFR 19 deletion or L858R mutation received first-line therapy with carboplatin area under the curve 6, pemetrexed 500 mg/m2, and bevacizumab 15 mg/kg once every 3 weeks for 4 cycles. Patients without disease progression during the induction therapy were randomly assigned 1:1 for maintenance therapy with pemetrexed 500 mg/m2 plus bevacizumab 15 mg/kg or bevacizumab 15 mg/kg once every 3 weeks until disease progression or unacceptable toxicity. The primary end point was overall survival (OS) after random assignment. RESULTS Between September 2010 and September 2015, 907 patients received induction therapy. Of those, 599 were randomly assigned: 298 received pemetrexed plus bevacizumab, and 301 received bevacizumab. The median OS was 23.3 v 19.6 months (hazard ratio [HR], 0.87; 95% CI, 0.73 to 1.05; 1-sided stratified log-rank P = .069). In the wild-type EGFR subset, the OS HR was 0.82 (95% CI, 0.68 to 0.99; 1-sided unstratified log-rank P = .020). The median progression-free survival (PFS) was 5.7 v 4.0 months (HR, 0.67; 95% CI, 0.57 to 0.79; 2-sided log-rank P < .001). The safety data were consistent with previous reports of treatment regimens. CONCLUSION In terms of the primary end point of OS, no statistically significant benefit was observed; however, PFS in the total patient population and OS in patients with wild-type EGFR was prolonged with the addition of pemetrexed to bevacizumab maintenance therapy.

A Case of EGFR-wild-type Adenocarcinoma of Recurrent Non-small Cell Lung Cancer Responding to Erlotinib

Haigan ◽  
2012 ◽  
Vol 52 (3) ◽  
pp. 315-319
Author(s):  
Masami Morimoto ◽  
Naoki Hino ◽  
Hisashi Matsuoka ◽  
Takanori Miyoshi ◽  
Masaru Tsuyuguchi
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Wild Type ◽  
Small Cell Lung

scholarly journals Erianthridin suppresses non-small-cell lung cancer cell metastasis through inhibition of Akt/mTOR/p70S6K signaling pathway

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Sutthaorn Pothongsrisit ◽  
Kuntarat Arunrungvichian ◽  
Yoshihiro Hayakawa ◽  
Boonchoo Sritularak ◽  
Supachoke Mangmool ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Cell Migration ◽  
Protein Kinase ◽  
Small Cell Lung Cancer ◽  
Cancer Metastasis ◽  
Small Cell ◽  
Migration And Invasion ◽  
Lung Cancer Cell ◽  
Small Cell Lung ◽  
Cell Metastasis

AbstractCancer metastasis is a major cause of the high mortality rate in lung cancer patients. The cytoskeletal rearrangement and degradation of extracellular matrix are required to facilitate cell migration and invasion and the suppression of these behaviors is an intriguing approach to minimize cancer metastasis. Even though Erianthridin (ETD), a phenolic compound isolated from the Thai orchid Dendrobium formosum exhibits various biological activities, the molecular mechanism of ETD for anti-cancer activity is unclear. In this study, we found that noncytotoxic concentrations of ETD (≤ 50 μM) were able to significantly inhibit cell migration and invasion via disruption of actin stress fibers and lamellipodia formation. The expression of matrix metalloproteinase-2 (MMP-2) and MMP-9 was markedly downregulated in a dose-dependent manner after ETD treatment. Mechanistic studies revealed that protein kinase B (Akt) and its downstream effectors mammalian target of rapamycin (mTOR) and p70 S6 kinase (p70S6K) were strongly attenuated. An in silico study further demonstrated that ETD binds to the protein kinase domain of Akt with both hydrogen bonding and van der Waals interactions. In addition, an in vivo tail vein injection metastasis study demonstrated a significant effect of ETD on the suppression of lung cancer cell metastasis. This study provides preclinical information regarding ETD, which exhibits promising antimetastatic activity against non-small-cell lung cancer through Akt/mTOR/p70S6K-induced actin reorganization and MMPs expression.

scholarly journals Correlation of Clinical Parameters with Intracranial Outcome in Non-Small Cell Lung Cancer Patients with Brain Metastases Treated with Pd-1/Pd-L1 Inhibitors as Monotherapy

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1562
Author(s):  
Konstantinos Rounis ◽  
Marcus Skribek ◽  
Dimitrios Makrakis ◽  
Luigi De Petris ◽  
Sofia Agelaki ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Brain Metastases ◽  
Small Cell Lung Cancer ◽  
Disease Progression ◽  
Cell Lung Cancer ◽  
Response Assessment ◽  
Small Cell ◽  
University Hospital ◽  
Response Analysis ◽  
Small Cell Lung

There is a paucity of biomarkers for the prediction of intracranial (IC) outcome in immune checkpoint inhibitor (ICI)-treated non-small cell lung cancer (NSCLC) patients (pts) with brain metastases (BM). We identified 280 NSCLC pts treated with ICIs at Karolinska University Hospital, Sweden, and University Hospital of Heraklion, Greece. The inclusion criteria for response assessment were brain metastases (BM) prior to ICI administration, radiological evaluation with CT or MRI for IC response assessment, PD-1/PD-L1 inhibitors as monotherapy, and no local central nervous system (CNS) treatment modalities for ≥3 months before ICI initiation. In the IC response analysis, 33 pts were included. Non-primary (BM not present at diagnosis) BM, odds ratio (OR): 13.33 (95% CI: 1.424–124.880, p = 0.023); no previous brain radiation therapy (RT), OR: 5.49 (95% CI: 1.210–25.000, p = 0.027); and age ≥70 years, OR: 6.19 (95% CI: 1.27–30.170, p = 0.024) were associated with increased probability of IC disease progression. Two prognostic groups (immunotherapy (I-O) CNS score) were created based on the abovementioned parameters. The I-O CNS poor prognostic group B exhibited a higher probability for IC disease progression, OR: 27.50 (95% CI: 2.88–262.34, p = 0.004). Age, CNS radiotherapy before the start of ICI treatment, and primary brain metastatic disease can potentially affect the IC outcome of NSCLC pts with BM.

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