•Osimertinib 80 mg showed limited efficacy for NSCLC with EGFR ex20ins mutations.•The mutation type-specific concentration-dependency of osimertinibwas highlighted.•This study proposes higher dose ...osimertinib for NSCLC with EGFR ex20ins mutations.
Several preclinical data proposed a potential efficacy of osimertinib, a third-generation EGFR tyrosine kinase inhibitor, for EGFR exon 20 insertion (EGFR ex20ins)-positive non-small cell lung cancer (NSCLC). However, reported case series and a retrospective study proposed controversial efficacy. The efficacy of osimertinib in EGFR ex20ins-positive NSCLC have not been well evaluated in prospective clinical trials. In this study, we performed a prospective, single-arm, multi-center, open-label, non-randomized phase I/II study to evaluate efficacy of osimertinib for EGFR ex20ins-positive NSCLC.
From August 2018 to January 2020, 14 NSCLC patients with EGFR ex20ins were enrolled, of whom 2 were excluded because they did not meet the inclusion criteria. Efficacy and safety of 80 mg osimertinib were evaluated. In addition, we performed a translational exploratory study to clarify the association of mutation type-specific drug sensitivity, osimertinib pharmacokinetic data, and clinical efficacy.
Of the evaluated patients, none experienced objective response, 7 experienced stable disease (58.3%), and 5 experienced disease progression (41.7%). The median progression free survival (PFS) was 3.8 months, and the median overall survival was 15.8 months. Interestingly, the exploratory study demonstrated statistically significant positive correlation between plasma osimertinib concentration/in vitro IC50 ratio and PFS (R = 0.9912, P = 0.0001), highlighting the mutation type-specific concentration-dependent efficacy of osimertinib for EGFR ex20ins-positive NSCLC.
Regular dose, 80 mg/day, of osimertinib has limited clinical activity in NSCLC patients with EGFR ex20ins. The translational study proposed the potential efficacy of higher dose osimertinib in a subgroup of EGFR ex20ins-positive NSCLC.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Small‐cell lung cancer (SCLC) accounts for approximately 15% of all lung cancers, and is characterized as extremely aggressive, often displaying rapid tumor growth and multiple organ metastases. In ...addition, the clinical outcome of SCLC patients is poor due to early relapse and acquired resistance to standard chemotherapy treatments. Hence, novel therapeutic strategies for the treatment of SCLC are urgently required. Accordingly, several molecular targeted therapies were evaluated in SCLC; however, they failed to improve the clinical outcome. The receptor tyrosine kinase MET is a receptor for hepatocyte growth factor (HGF), and aberrant activation of HGF/MET signaling is known as one of the crucial mechanisms enabling cancer progression and invasion. Here, we found that the HGF/MET signaling was aberrantly activated in chemoresistant or chemorelapsed SCLC cell lines (SBC‐5, DMS273, and DMS273‐G3H) by the secretion of HGF and/or MET copy number gain. A cell‐based in vitro assay revealed that HGF/MET inhibition, induced either by MET inhibitors (crizotinib and golvatinib), or by siRNA‐mediated knockdown of HGF or MET, constrained growth of chemoresistant SCLC cells through the inhibition of ERK and AKT signals. Furthermore, treatment with either crizotinib or golvatinib suppressed the systemic metastasis of SBC‐5 cell tumors in natural killer cell‐depleted SCID mice, predominantly through cell cycle arrest. These findings reveal the therapeutic potential of targeting the HGF/MET pathway for inhibition, to constrain tumor progression of SCLC cells showing aberrant activation of HGF/MET signaling. We suggest that it would be clinically valuable to further investigate HGF/MET‐mediated signaling in SCLC cells.
In the present study, we demonstrated that HGF/MET signaling was aberrantly activated in chemo‐resistant or chemo‐relapsed SCLC cell lines by the secretion of HGF and/or MET copy number gain. Furthermore, the MET inhibitors crizotinib and golvatinib were able to inhibit cell growth, and prevent systemic metastasis of SCLC cells in vivo, predominantly via cell cycle arrest. These findings indicate that inhibition of HGF/MET signaling may constrain tumor progression of SCLC cells exhibiting aberrant activation of the HGF/MET pathway.
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Crizotinib, a first‐generation anaplastic lymphoma kinase (ALK) tyrosine‐kinase inhibitor, is known to be effective against echinoderm microtubule‐associated protein‐like 4 (EML4)‐ALK‐positive ...non‐small cell lung cancers. Nonetheless, the tumors subsequently become resistant to crizotinib and recur in almost every case. The mechanism of the acquired resistance needs to be deciphered. In this study, we established crizotinib‐resistant cells (A925LPE3‐CR) via long‐term administration of crizotinib to a mouse model of pleural carcinomatous effusions; this model involved implantation of the A925LPE3 cell line, which harbors the EML4‐ALK gene rearrangement. The resistant cells did not have the secondary ALK mutations frequently occurring in crizotinib‐resistant cells, and these cells were cross‐resistant to alectinib and ceritinib as well. In cell clone #2, which is one of the clones of A925LPE3‐CR, crizotinib sensitivity was restored via the inhibition of epidermal growth factor receptor (EGFR) by means of an EGFR tyrosine‐kinase inhibitor (erlotinib) or an anti‐EGFR antibody (cetuximab) in vitro and in the murine xenograft model. Cell clone #2 did not have an EGFR mutation, but the expression of amphiregulin (AREG), one of EGFR ligands, was significantly increased. A knockdown of AREG with small interfering RNAs restored the sensitivity to crizotinib. These data suggest that overexpression of EGFR ligands such as AREG can cause resistance to crizotinib, and that inhibition of EGFR signaling may be a promising strategy to overcome crizotinib resistance in EML4‐ALK lung cancer.
In the present study, we induced crizotinib resistant EML4‐ALK lung cancer cells in vivo model, to identify novel resistance mechanism. We found amphiregulin (AREG), an EGFR ligand, is largely responsible for the activation of EGFR in an autocrine manner and in turn leads to resistance to crizotinib. While several studies have reported that EGF, TGF‐α, and HB‐EGF are EGFR ligands that trigger ALK‐TKI resistance, the present study is the first to reveal that AREG triggers ALK‐TKI resistance.
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•A regression model for forecasting the total amount of airborne pollen was developed.•Total airborne birch pollen could be estimated from weather data of previous years.•Three ...meteorological variables in June of the previous 3 years led the best result.•An applicability of the forecasting model was verified by using the observed data.
The birch tree (genus Betula L.) disperses airborne pollen annually from April to June, causing severe symptoms in pollinosis sufferers. Because of interannual variations in pollen levels, there is an urgent need to develop a forecasting model with greater precision in order to provide accurate information to patients and medical personnel regarding airborne pollen levels. We developed an algorithm for forecasting the total amount of airborne birch pollen. This equation suggested that the total amount of airborne pollen in a given season could be estimated using only the meteorological data from previous years. In order to discover potential predictive relationships, a data set including airborne pollen data from 1996 to 2015 and meteorological data from 1990 to 2014 was used to construct forecasting models. Statistical evaluation results were examined to select the optimal model, showing that forecasting models obtained the highest accuracy when using meteorological data from June and the best model performance was achieved using the average daily maximum air temperature and solar radiation of the previous five years. We also developed an extended model that included relative humidity, which demonstrated better predictive capability. These findings clarify that a model with greater predictive power can be constructed using the meteorological conditions from the previous five years. In order to assess this conclusion, the algorithm was tested by forecasting the total amount of airborne birch pollen in Japan with good results.
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The third‐generation epidermal growth factor receptor tyrosine kinase inhibitor (EGFR‐TKI) osimertinib is approved for untreated, or previously EGFR‐TKI–treated T790M‐positive EGFR‐mutated non‐small ...cell lung carcinoma (NSCLC). We investigated the heterogeneity of responses to osimertinib and its underlying mechanisms. A patient with EGFR‐L858R–mutated NSCLC was treated with erlotinib. Following treatment, he developed brain and multiple bone metastases and was eventually diagnosed with NSCLC with EGFR‐T790M mutation. The responses of various tumor specimens to osimertinib were heterogeneous. We investigated EGFR‐T790M and MET amplification using PCR and FISH in autopsy specimens of the cervical spine, lumbar spine, and brain. We established the KNZ osimertinib‐resistant (KNZ_OR) tumor cell line with MET amplification using a cervical spine lesion that was intrinsically resistant to osimertinib. We evaluated the effects of MET knockdown and MET inhibitor on KNZ_OR cell sensitivity to osimertinib in vitro and in vivo. Osimertinib‐resistant lesions (cervical spine and brain) showed EGFR‐L858R and MET amplification, but not EGFR‐T790M, whereas osimertinib‐sensitive lesions (lumbar spine) showed EGFR‐L858R and ‐T790, but not MET amplification. Osimertinib decreased the association of amplified MET with L858R‐mutated EGFR but increased that with human epidermal growth factor receptor 3 in KNZ_OR cells. MET knockdown or MET inhibitor sensitized KNZ_OR cells to osimertinib in vitro, indicating that MET amplification induced osimertinib resistance. Combination with osimertinib plus crizotinib induced tumor shrinkage in the KNZ_OR xenograft model. Hence, MET amplification might induce heterogeneous responses to osimertinib in EGFR‐mutated NSCLC. Further investigations on mutated EGFR and amplified MET might lead to the development of effective therapies.
MET amplification leads to osimertinib resistance and association MET with mutated EGFR may be a novel finding.
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EGFR tyrosine kinase inhibitors cause dramatic responses in EGFR-mutant lung cancer, but resistance universally develops. The involvement of β-catenin in EGFR TKI resistance has been previously ...reported, however, the precise mechanism by which β-catenin activation contributes to EGFR TKI resistance is not clear. Here, we show that EGFR inhibition results in the activation of β-catenin signaling in a Notch3-dependent manner, which facilitates the survival of a subset of cells that we call "adaptive persisters". We previously reported that EGFR-TKI treatment rapidly activates Notch3, and here we describe the physical association of Notch3 with β-catenin, leading to increased stability and activation of β-catenin. We demonstrate that the combination of EGFR-TKI and a β-catenin inhibitor inhibits the development of these adaptive persisters, decreases tumor burden, improves recurrence free survival, and overall survival in xenograft models. These results supports combined EGFR-TKI and β-catenin inhibition in patients with EGFR mutant lung cancer.
Primary malignant melanoma (MM) of the mediastinum is rare, and there is a lack of consensus regarding the preferred treatment because non-cutaneous MM demonstrates an inferior response to systemic ...therapy. Herein, we describe the case of a 73-year-old man with MM of the anterior mediastinum with multiple liver metastases. Even though the size of lesions increased rapidly following diagnosis, nivolumab monotherapy caused remarkable tumor shrinkage. This is the first report of mediastinal MM showing a significant response to nivolumab. We, therefore, suggest that immunotherapy may be one of the treatment options for primary mediastinal MM.
Using our newly developed ultrafast camera described in the companion paper, we reduced the data acquisition periods required for photoactivation/photoconversion localization microscopy (PALM, using ...mEos3.2) and direct stochastic reconstruction microscopy (dSTORM, using HMSiR) by a factor of ≈30 compared with standard methods, for much greater view-fields, with localization precisions of 29 and 19 nm, respectively, thus opening up previously inaccessible spatiotemporal scales to cell biology research. Simultaneous two-color PALM-dSTORM and PALM-ultrafast (10 kHz) single fluorescent-molecule imaging-tracking has been realized. They revealed the dynamic nanoorganization of the focal adhesion (FA), leading to the compartmentalized archipelago FA model, consisting of FA-protein islands with broad diversities in size (13-100 nm; mean island diameter ≈30 nm), protein copy numbers, compositions, and stoichiometries, which dot the partitioned fluid membrane (74-nm compartments in the FA vs. 109-nm compartments outside the FA). Integrins are recruited to these islands by hop diffusion. The FA-protein islands form loose ≈320 nm clusters and function as units for recruiting FA proteins.
Abstract The nuclear receptor, pregnane X receptor (PXR), is a ligand-dependent transcription factor that regulates genes involved in xenobiotic metabolism. Recent studies have shown that PXR ...activation may affect energy metabolism as well as the endocrine and immune systems. In this study, we characterized and compared the agonistic activities of a variety of pesticides against human PXR (hPXR) and mouse PXR (mPXR). We tested the hPXR and mPXR agonistic activity of 200 pesticides (29 organochlorines, 11 diphenyl ethers, 56 organophosphorus pesticides, 12 pyrethroids, 22 carbamates, 12 acid amides, 7 triazines, 7 ureas, and 44 others) by reporter gene assays using COS-7 simian kidney cells. Of the 200 pesticides tested, 106 and 93 activated hPXR and mPXR, respectively, and a total of 111 had hPXR and/or mPXR agonistic activity with greater or lesser inter-species differences. Although all of the pyrethroids and most of the organochlorines and acid amides acted as PXR agonists, a wide range of pesticides with diverse structures also showed hPXR and/or mPXR agonistic activity. Among the 200 pesticides, pyributicarb, pretilachlor, piperophos and butamifos for hPXR, and phosalone, prochloraz, pendimethalin, and butamifos for mPXR, acted as particularly potent activators at low concentrations in the order of 10−8 –10−7 M. In addition, we found that several organophosphorus oxon- and pyributicarb oxon-metabolites decreased PXR activation potency compared to their parent compounds. These results suggest that a large number of structurally diverse pesticides and their metabolites possess PXR-mediated transcriptional activity, and their ability to do so varies in a species-dependent manner in humans and mice.
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Tropomyosin receptor kinase (TRK) inhibitors have demonstrated histology‐agnostic efficacy in patients with neurotrophic receptor tyrosine kinase (NTRK) gene fusion. Although responses to TRK ...inhibitors can be dramatic and durable, duration of response may eventually be limited by acquired resistance via several mechanisms, including resistance mutations such as NTRK1‐G595R. Repotrectinib is a second‐generation TRK inhibitor, which is active against NTRK1‐G595R. However, its efficacy against entrectinib‐resistant tumors has not been fully elucidated. In the present study, we established entrectinib‐resistant tumor cells (M3B) in a brain metastasis model inoculated with NTRK1‐rearranged KM12SM cells and examined the sensitivity of M3B cells to repotrectinib. While M3B cells harbored the NTRK1‐G595R mutation, they were unexpectedly resistant to repotrectinib. The resistance was due to extracellular signal–regulated kinase (ERK) reactivation partially mediated by epidermal growth factor receptor (EGFR) activation. We further demonstrate that the triplet combination of repotrectinib, EGFR inhibitor, and MEK inhibitor could sensitize M3B cells in vitro as well as in a brain metastasis model. These results indicate that resistant mutations, such as NTRK1‐G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib‐resistant tumors, thereby causing resistance to second‐generation inhibitor repotrectinib. These findings highlight the importance of intensive examinations to identify resistance mechanisms and application of the appropriate combination treatment to circumvent the resistance.
We explored the resistance mechanism to tropomyosin receptor kinase (TRK) inhibitors. We demonstrated that resistant mutations, such as NTRK1‐G595R, and alternative pathway activation, such as ERK activation, could simultaneously occur in entrectinib‐resistant tumors, thereby causing resistance to entrectinib as well as repotrectinib, and that this resistance could be surmounted by triple inhibitions to TRK, EGFR, and ERK.
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