scholarly journals Targeting the Src Pathway Enhances the Efficacy of Selective FGFR Inhibitors in Urothelial Cancers with FGFR3 Alterations

2020 ◽  
Vol 21 (9) ◽  
pp. 3214 ◽  
Author(s):  
Nadia Carvalho Lima ◽  
Eliza Atkinson ◽  
Tom D. Bunney ◽  
Matilda Katan ◽  
Paul H. Huang
Keyword(s):  
Urothelial Carcinoma ◽  
Kinase Inhibitor ◽  
Unmet Need ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Molecular Alterations ◽  
Intrinsic Drug Resistance ◽  
Nih 3T3 ◽  
Src Pathway

Selective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our data provide preclinical rationale that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in urothelial cancer patients with FGFR3 molecular alterations

scholarly journals Targeting the Src pathway enhances the efficacy of selective FGFR inhibitors in cancers with FGFR3 alterations

2020 ◽  
Author(s):  
Nadia Carvalho Lima ◽  
Eliza Atkinson ◽  
Tom D Bunney ◽  
Matilda Katan ◽  
Paul H. Huang
Keyword(s):  
Urothelial Carcinoma ◽  
Kinase Inhibitor ◽  
Unmet Need ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Molecular Alterations ◽  
Intrinsic Drug Resistance ◽  
Nih 3T3 ◽  
Src Pathway

AbstractSelective FGFR inhibitors such as infigratinib (BGJ398) and erdafitinib (JNJ-42756493) have been evaluated in clinical trials for cancers with FGFR3 molecular alterations, particularly in urothelial carcinoma patients. However, a substantial proportion of these patients (up to 50%) display intrinsic resistance to these drugs and receive minimal clinical benefit. There is thus an unmet need for alternative therapeutic strategies to overcome primary resistance to selective FGFR inhibitors. In this study, we demonstrate that cells expressing cancer-associated activating FGFR3 mutants and the FGFR3-TACC3 fusion showed primary resistance to infigratinib in long-term colony formation assays in both NIH-3T3 and urothelial carcinoma models. We find that expression of these FGFR3 molecular alterations resulted in elevated constitutive Src activation compared to wildtype FGFR3 and that cells co-opted this pathway as a means to achieve intrinsic resistance to infigratinib. Targeting the Src pathway with low doses of the kinase inhibitor dasatinib synergistically sensitized multiple urothelial carcinoma lines harbouring endogenous FGFR3 alterations to infigratinib. Our preclinical data provides evidence that supports the use of dasatinib in combination with selective FGFR inhibitors as a means to overcome intrinsic drug resistance in the salvage therapy setting in cancer patients with FGFR3 molecular alterations.

scholarly journals Long‐term safety and efficacy of delgocitinib ointment, a topical Janus kinase inhibitor, in adult patients with atopic dermatitis

2019 ◽  
Vol 47 (2) ◽  
pp. 114-120 ◽  
Author(s):  
Hidemi Nakagawa ◽  
Osamu Nemoto ◽  
Atsuyuki Igarashi ◽  
Hidehisa Saeki ◽  
Ryusei Murata ◽  
...  
Keyword(s):  
Atopic Dermatitis ◽  
Kinase Inhibitor ◽  
Janus Kinase ◽  
Adult Patients ◽  
Janus Kinase Inhibitor ◽  
Safety And Efficacy

scholarly journals Are the needs of people with multiple long-term conditions being met? Evidence from the 2018 General Practice Patient Survey

BMJ Open ◽  
2020 ◽  
Vol 10 (11) ◽  
pp. e041569
Author(s):  
Lucina Rolewicz ◽  
Eilís Keeble ◽  
Charlotte Paddison ◽  
Sarah Scobie
Keyword(s):  
General Practice ◽  
Unmet Need ◽  
Patient Survey ◽  
Secondary Outcome ◽  
Community Based ◽  
Long Term Conditions ◽  
Local Services ◽  
Community Based Services ◽  
Practice Patient

ObjectivesTo investigate individual, practice and area level variation in patient-reported unmet need among those with long-term conditions, in the context of general practice (GP) appointments and support from community-based services in England.DesignCross-sectional study using data from 199 150 survey responses.SettingPrimary care and community-based services.ParticipantsRespondents to the 2018 English General Practice Patient Survey with at least one long-term condition.Primary and secondary outcome measuresThe primary outcomes were the levels of unmet need in GP and local services among patients with multiple long-term conditions. Secondary outcomes were the proportion of variation explained by practice and area-level factors.ResultsThere was no relationship between needs being fully met in patients’ last practice appointment and number of long-term conditions once sociodemographic characteristics and health status were taken into account (5+conditions−OR=1.04, 95% CI 0.99 to 1.09), but there was a relationship for having enough support from local services to manage conditions (5+conditions−OR=0.84, 95% CI 0.80 to 0.88). Patients with multimorbidity that were younger, non-white or frail were less likely to have their needs fully met, both in GP and from local services. Differences between practices and local authorities explained minimal variation in unmet need.ConclusionsLevels of unmet need are high, particularly for support from community services to manage multiple conditions. Patients who could be targeted for support include people who feel socially isolated, and those who have difficulties with their day-to-day living. Younger patients and certain ethnic groups with multimorbidity are also more likely to have unmet needs. Increased personalisation and coordination of care among these groups may help in addressing their needs.

scholarly journals Altered mRNA Levels of Stress-Related Peptides in Mouse Hippocampus and Caudate-Putamen in Withdrawal after Long-Term Intermittent Exposure to Tobacco Smoke or Electronic Cigarette Vapour

2021 ◽  
Vol 22 (2) ◽  
pp. 599
Author(s):  
Lucia Carboni ◽  
Luisa Ponzoni ◽  
Daniela Braida ◽  
Mariaelvina Sala ◽  
Cecilia Gotti ◽  
...  
Keyword(s):  
Public Health Problem ◽  
Mrna Levels ◽  
Obsessive Compulsive ◽  
Bdnf Mrna ◽  
Object Recognition Test ◽  
Caudate Putamen ◽  
Molecular Alterations ◽  
Marble Burying ◽  
Cigarette Withdrawal

Nicotine addiction is a severe public health problem. The aim of this study was to investigate the alterations in key neurotransmissions after 60 days of withdrawal from seven weeks of intermittent cigarette smoke, e-cigarette vapours, or an e-cigarette vehicle. In the nicotine withdrawal groups, increased depressive and anxiety/obsessive–compulsive-like behaviours were demonstrated in the tail suspension, sucrose preference and marble burying tests. Cognitive impairments were detected in the spatial object recognition test. A significant increase in Corticotropin-releasing factor (Crf) and Crf1 mRNA levels was observed, specifically after cigarette withdrawal in the caudate-putamen nucleus (CPu). The nociceptin precursor levels were reduced by cigarette (80%) and e-cigarette (50%) withdrawal in the CPu. The delta opioid receptor showed a significant reduction in the hippocampus driven by the exposure to an e-cigarette solubilisation vehicle, while the mRNA levels doubled in the CPu of mice that had been exposed to e-cigarettes. Withdrawal after exposure to e-cigarette vapour induced a 35% Bdnf mRNA decrease in the hippocampus, whereas Bdnf was augmented by 118% by cigarette withdrawal in the CPu. This study shows that long-term withdrawal-induced affective and cognitive symptoms associated to lasting molecular alterations in peptidergic signalling may determine the impaired neuroplasticity in the hippocampal and striatal circuitry.

scholarly journals Apoferritin/Vandetanib Association Is Long-Term Stable but Does Not Improve Pharmacological Properties of Vandetanib

2021 ◽  
Vol 22 (8) ◽  
pp. 4250
Author(s):  
Kateřina Jáklová ◽  
Tereza Feglarová ◽  
Simona Rex ◽  
Zbyněk Heger ◽  
Tomáš Eckschlager ◽  
...  
Keyword(s):  
Cell Lines ◽  
Targeted Delivery ◽  
Medullary Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Medullary Thyroid ◽  
Long Term Stability ◽  
Carcinoma Cell Lines ◽  
Average Size ◽  
Thyroid Carcinoma Cell

A tyrosine kinase inhibitor, vandetanib (Van), is an anticancer drug affecting the signaling of VEGFR, EGFR and RET protooncogenes. Van is primarily used for the treatment of advanced or metastatic medullary thyroid cancer; however, its usage is significantly limited by side effects, particularly cardiotoxicity. One approach to minimize them is the encapsulation or binding of Van in- or onto a suitable carrier, allowing targeted delivery to tumor tissue. Herein, we constructed a nanocarrier based on apoferritin associated with Van (ApoVan). Based on the characteristics obtained by analyzing the average size, the surface ζ-potential and the polydispersive index, ApoVan nanoparticles exhibit long-term stability and maintain their morphology. Experiments have shown that ApoVan complex is relatively stable during storage. It was found that Van is gradually released from its ApoVan form into the neutral environment (pH 7.4) as well as into the acidic environment (pH 6.5). The effect of free Van and ApoVan on neuroblastoma and medullary thyroid carcinoma cell lines revealed that both forms were toxic in both used cell lines, and minimal differences between ApoVan and Van were observed. Thus, we assume that Van might not be encapsulated into the cavity of apoferritin, but instead only binds to its surface.

scholarly journals Inhibition of the Myocardin-Related Transcription Factor Pathway Increases Efficacy of Trametinib in NRAS-Mutant Melanoma Cell Lines

Cancers ◽  
2021 ◽  
Vol 13 (9) ◽  
pp. 2012
Author(s):  
Kathryn M. Appleton ◽  
Charuta C. Palsuledesai ◽  
Sean A. Misek ◽  
Maja Blake ◽  
Joseph Zagorski ◽  
...  
Keyword(s):  
Cell Lines ◽  
Melanoma Cell ◽  
Therapeutic Potential ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Intrinsic Resistance ◽  
Primary Resistance ◽  
Induced Apoptosis ◽  
Melanoma Cell Lines

The Ras/MEK/ERK pathway has been the primary focus of targeted therapies in melanoma; it is aberrantly activated in almost 80% of human cutaneous melanomas (≈50% BRAFV600 mutations and ≈30% NRAS mutations). While drugs targeting the MAPK pathway have yielded success in BRAFV600 mutant melanoma patients, such therapies have been ineffective in patients with NRAS mutant melanomas in part due to their cytostatic effects and primary resistance. Here, we demonstrate that increased Rho/MRTF-pathway activation correlates with high intrinsic resistance to the MEK inhibitor, trametinib, in a panel of NRAS mutant melanoma cell lines. A combination of trametinib with the Rho/MRTF-pathway inhibitor, CCG-222740, synergistically reduced cell viability in NRAS mutant melanoma cell lines in vitro. Furthermore, the combination of CCG-222740 with trametinib induced apoptosis and reduced clonogenicity in SK-Mel-147 cells, which are highly resistant to trametinib. These findings suggest a role of the Rho/MRTF-pathway in intrinsic trametinib resistance in a subset of NRAS mutant melanoma cell lines and highlight the therapeutic potential of concurrently targeting the Rho/MRTF-pathway and MEK in NRAS mutant melanomas.

scholarly journals Tyrosine Kinase Inhibitor Induced Isolated Pericardial Effusion

2015 ◽  
Vol 8 (1) ◽  
pp. 88-93 ◽  
Author(s):  
Vineet Agrawal ◽  
Eric S. Christenson ◽  
Margaret M. Showel
Keyword(s):  
Primary Care ◽  
Pericardial Effusion ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
Early Recognition ◽  
Primary Care Providers ◽  
Incidence Rates ◽  
Term Therapy ◽  
Care Providers

Long-term therapy with tyrosine kinase inhibitors (TKI) has resulted in improved outcomes for patients suffering from Bcr-Abl fusion protein-harboring leukemias. As a result, a growing population of patients on TKI therapy present to their primary care providers. In this case, we report on the case of a 62-year-old male who presented with a symptomatic pericardial effusion. After pericardiocentesis, malignancy and infectious etiologies were excluded. The pericardial effusion was attributed to his TKI, with a transition of this medication to a different TKI. A repeat evaluation 1 month following the withdrawal of the offending agent showed no recurrence of his pericardial effusion on echocardiogram. In this report, we will highlight a rare but important side effect of TKI therapy before discussing its purported mechanisms and differing incidence rates. Early recognition of serosal inflammation related to long-term TKI therapy by primary care providers is important in preventing patient morbidity and mortality.

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