scholarly journals Perturbation biology nominates upstream–downstream drug combinations in RAF inhibitor resistant melanoma cells

eLife ◽  
2015 ◽  
Vol 4 ◽  
Author(s):  
Anil Korkut ◽  
Weiqing Wang ◽  
Emek Demir ◽  
Bülent Arman Aksoy ◽  
Xiaohong Jing ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Network Models ◽  
Clinical Problem ◽  
Melanoma Cells ◽  
Drug Combinations ◽  
Protein Kinase Inhibitors ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Important Clinical Problem ◽  
Targeted Cancer Therapies

Resistance to targeted cancer therapies is an important clinical problem. The discovery of anti-resistance drug combinations is challenging as resistance can arise by diverse escape mechanisms. To address this challenge, we improved and applied the experimental-computational perturbation biology method. Using statistical inference, we build network models from high-throughput measurements of molecular and phenotypic responses to combinatorial targeted perturbations. The models are computationally executed to predict the effects of thousands of untested perturbations. In RAF-inhibitor resistant melanoma cells, we measured 143 proteomic/phenotypic entities under 89 perturbation conditions and predicted c-Myc as an effective therapeutic co-target with BRAF or MEK. Experiments using the BET bromodomain inhibitor JQ1 affecting the level of c-Myc protein and protein kinase inhibitors targeting the ERK pathway confirmed the prediction. In conclusion, we propose an anti-cancer strategy of co-targeting a specific upstream alteration and a general downstream point of vulnerability to prevent or overcome resistance to targeted drugs.

Kinase Inhibitors Targeting Anti-angiogenesis as Anti-cancer Therapies

2012 ◽  
Vol 1 (4) ◽  
pp. 335-346 ◽  
Author(s):  
Jing Liu ◽  
Feiyang Liu ◽  
David L. Waller ◽  
Junfeng Wang ◽  
Qingsong Liu
Keyword(s):  
Kinase Inhibitors ◽  
Cancer Therapies ◽  
Anti Cancer

scholarly journals Patient-derived models of acquired resistance can identify effective drug combinations for cancer

Science ◽  
2014 ◽  
Vol 346 (6216) ◽  
pp. 1480-1486 ◽  
Author(s):  
Adam S. Crystal ◽  
Alice T. Shaw ◽  
Lecia V. Sequist ◽  
Luc Friboulet ◽  
Matthew J. Niederst ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitors ◽  
Acquired Resistance ◽  
Growth Factor Receptor ◽  
Drug Combinations ◽  
Effective Drug ◽  
Cancer Therapies ◽  
Lung Cancer Patients ◽  
Anaplastic Lymphoma ◽  
Culture Models

Targeted cancer therapies have produced substantial clinical responses, but most tumors develop resistance to these drugs. Here, we describe a pharmacogenomic platform that facilitates rapid discovery of drug combinations that can overcome resistance. We established cell culture models derived from biopsy samples of lung cancer patients whose disease had progressed while on treatment with epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors and then subjected these cells to genetic analyses and a pharmacological screen. Multiple effective drug combinations were identified. For example, the combination of ALK and MAPK kinase (MEK) inhibitors was active in an ALK-positive resistant tumor that had developed a MAP2K1 activating mutation, and the combination of EGFR and fibroblast growth factor receptor (FGFR) inhibitors was active in an EGFR mutant resistant cancer with a mutation in FGFR3. Combined ALK and SRC (pp60c-src) inhibition was effective in several ALK-driven patient-derived models, a result not predicted by genetic analysis alone. With further refinements, this strategy could help direct therapeutic choices for individual patients.

scholarly journals Potential drug-drug interactions in the psychiatric hospital: Frequency analysis

2019 ◽  
Vol 5 (4) ◽  
pp. 1-6
Author(s):  
Oleg O. Kirilochev ◽  
Inna P. Dorfman ◽  
Adelya R. Umerova ◽  
Svetlana E. Bataeva
Keyword(s):  
Drug Interactions ◽  
Clinical Significance ◽  
Psychiatric Hospital ◽  
Psychiatric Inpatient ◽  
Clinical Problem ◽  
Drug Combinations ◽  
Drug Prescriptions ◽  
Inpatient Setting ◽  
Potential Drug ◽  
Important Clinical Problem

Introduction: Drug-drug interactions are an important clinical problem in pharmacotherapy. This study is focused on different types of drugs used in a psychiatric hospital. Materials and methods: The pharmacoepidemiological study included the analysis of medical records of 500 psychiatric inpatients. The patients were divided into 2 groups: under 65 and over 65 years of age. All the drug prescriptions were analyzed to identify the combinations of drugs that can induce drug-drug interactions and determine their clinical significance. Results and discussion: Over 77% of hospitalized patients were administered drug combinations that could induce drug-drug interactions, most of which were of moderate clinical significance. A reliable association was found between the patient’s age, the clinical significance of drug-drug interactions, and the pharmacotherapy structure. The most common irrational drug combinations were identified. Conclusion: Timely analysis of drug prescriptions for potential drug-drug interactions can enhance the safety of pharmacotherapy and decrease the risk of adverse drug reactions in the psychiatric inpatient setting.

Receptor-mediated endocytosis of urokinase-type plasminogen activator is regulated by cAMP-dependent protein kinase

1997 ◽  
Vol 110 (12) ◽  
pp. 1395-1402 ◽  
Author(s):  
L. Goretzki ◽  
B.M. Mueller
Keyword(s):  
Protein Kinase ◽  
Plasminogen Activator ◽  
Kinase Inhibitors ◽  
Melanoma Cells ◽  
Protein Kinase Inhibitors ◽  
Dependent Protein Kinase ◽  
Camp Dependent Protein Kinase ◽  
Type Plasminogen Activator ◽  
Urokinase Type Plasminogen Activator ◽  
Dependent Protein

Internalization of the urokinase-type plasminogen activator (uPA) requires two receptors, the uPA receptor (uPAR) and the low density lipoprotein receptor-related protein (LRP)/alpha2-macroglobulin (alpha2M) receptor. Here, we address whether protein kinases are involved in the internalization of uPA by human melanoma cells. Initially, we found that the internalization of uPA was significantly inhibited by the serine/threonine protein kinase inhibitors staurosporine, K-252a and H-89, but not by the tyrosine kinase inhibitors, genistein and lavendustin A. Internalization of uPA was also inhibited by a pseudosubstrate peptide for cAMP-dependent protein kinase (PKA), but not by a pseudosubstrate peptide for protein kinase C. We confirmed a requirement for PKA-activity and implicated a specific isoform by using an antisense oligonucleotide against the regulatory subunit RI alpha of PKA which suppresses PKA-I activity. Exposure of cells to this oligonucleotide led to a specific, dose-dependent decrease in RI alpha protein and to a significant inhibition in the rate of uPA internalization. We further demonstrate that treatment of melanoma cells with either H-89 or PKA RI alpha antisense oligonucleotides also resulted in a decreased internalization of two other ligands of LRP, activated alpha2M and lactoferrin, indicating that PKA activity is associated with LRP. Finally, we demonstrate that PKA activity is also required for the internalization of transferrin, but not for the internalization of the epidermal growth factor or adenovirus 2, suggesting that in melanoma cells, PKA activity is not generally required for clathrin-mediated endocytosis, but is rather associated with specific internalization receptors.

Dermatological side effects of immunotherapy drugs and targeted cancer therapies: Importance of dermatology and oncology collaboration

2020 ◽  
pp. 107815522097062
Author(s):  
Uğur Çelik ◽  
Ertuğrul H Aydemir ◽  
Burhan Engin ◽  
Muazzez Ç Oba ◽  
Mesut Yılmaz ◽  
...  
Keyword(s):  
Side Effects ◽  
Outpatient Clinic ◽  
Targeted Therapies ◽  
Side Effect ◽  
Common Side Effect ◽  
Cancer Therapies ◽  
Anti Cancer ◽  
Targeted Cancer Therapies ◽  
Dermatological Side Effects ◽  
Skin Side Effects

Introduction Novel anti-cancer drugs such as targeted cancer therapies and immune check-point inhibitors (ICIs) have adverse events, especially concerning the skin. The aim of this study is to report an overview of the commonly consulted dermatological side effects of ICIs and targeted cancer therapies in clinical practice, along with their management. Methods In this single-center study, we evaluated consecutive oncological patients who were referred from the oncology outpatient clinic to the dermatology outpatient clinic due to skin side effects of ICIs and targeted therapies. All patients were examined and treated at the same day of referral by experienced dermatologists. Patient characteristics, clinical findings, diagnostic workups and treatments were retrieved from outpatient records. Results Sixty three patients were enrolled. Most common diagnoses were lung carcinoma, melanoma and colon carcinoma. Fifty patients (79%) were using targeted therapies while 13 (21%) were using ICIs. Xerosis was the most common side effect (44%), followed by acneiform rash, paronychia, eczema and pruritus. Majority of the side effects were grade 2 and 3. Psoriasis was a common side effect of ICIs. One patient had a newly developed dysplastic nevus on vemurafenib treatment. Oncological treatment was not withheld in any of the patients. Conclusions This study revealed the most commonly consulted skin side effects of novel anti-cancer drugs and their management in daily practice. We underlie the importance of collaborative work of oncology and dermatology professionals as early management of cutaneous side effects of targeted therapies and ICIs improves patient outcomes.

scholarly journals Evaluation of Protein Kinase Inhibitors with PLK4 Cross-Over Potential in a Pre-Clinical Model of Cancer

2019 ◽  
Vol 20 (9) ◽  
pp. 2112 ◽  
Author(s):  
Amreena Suri ◽  
Anders W. Bailey ◽  
Maurício T. Tavares ◽  
Hendra Gunosewoyo ◽  
Connor P. Dyer ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Protein Kinase Inhibitors ◽  
Physiochemical Properties ◽  
Clinical Model ◽  
Anti Cancer ◽  
Brain Exposure ◽  
Dividing Cells ◽  
A Cell ◽  
Embryonal Brain

Polo-like kinase 4 (PLK4) is a cell cycle-regulated protein kinase (PK) recruited at the centrosome in dividing cells. Its overexpression triggers centrosome amplification, which is associated with genetic instability and carcinogenesis. In previous work, we established that PLK4 is overexpressed in pediatric embryonal brain tumors (EBT). We also demonstrated that PLK4 inhibition exerted a cytostatic effect in EBT cells. Here, we examined an array of PK inhibitors (CFI-400945, CFI-400437, centrinone, centrinone-B, R-1530, axitinib, KW-2449, and alisertib) for their potential crossover to PLK4 by comparative structural docking and activity inhibition in multiple established embryonal tumor cell lines (MON, BT-12, BT-16, DAOY, D283). Our analyses demonstrated that: (1) CFI-400437 had the greatest impact overall, but similar to CFI-400945, it is not optimal for brain exposure. Also, their phenotypic anti-cancer impact may, in part, be a consequence of the inhibition of Aurora kinases (AURKs). (2) Centrinone and centrinone B are the most selective PLK4 inhibitors but they are the least likely to penetrate the brain. (3) KW-2449, R-1530 and axitinib are the ones predicted to have moderate-to-good brain penetration. In conclusion, a new selective PLK4 inhibitor with favorable physiochemical properties for optimal brain exposure can be beneficial for the treatment of EBT.

Molecular mechanisms for vascular complications of targeted cancer therapies

2016 ◽  
Vol 130 (20) ◽  
pp. 1763-1779 ◽  
Author(s):  
Srila Gopal ◽  
Kenneth B. Miller ◽  
Iris Z. Jaffe
Keyword(s):  
Cancer Patients ◽  
Molecular Mechanisms ◽  
Cell Function ◽  
Vascular Complications ◽  
Vascular Complication ◽  
Cancer Therapies ◽  
Vegf Inhibitors ◽  
Increased Risk ◽  
Anti Cancer ◽  
Targeted Cancer Therapies

Molecularly targeted anti-cancer therapies have revolutionized cancer treatment by improving both quality of life and survival in cancer patients. However, many of these drugs are associated with cardiovascular toxicities that are sometimes dose-limiting. Moreover, the long-term cardiovascular consequences of these drugs, some of which are used chronically, are not yet known. Although the scope and mechanisms of the cardiac toxicities are better defined, the mechanisms for vascular toxicities are only beginning to be elucidated. This review summarizes what is known about the vascular adverse events associated with three classes of novel anti-cancer therapies: vascular endothelial growth factor (VEGF) inhibitors, breakpoint cluster-Abelson (BCR-ABL) kinase inhibitors used to treat chronic myelogenous leukaemia (CML) and immunomodulatory agents (IMiDs) used in myeloma therapeutics. Three of the best described vascular toxicities are reviewed including hypertension, increased risk of acute cardiovascular ischaemic events and arteriovenous thrombosis. The available data regarding the mechanism by which each therapy causes vascular complication are summarized. When data are limited, potential mechanisms are inferred from the known effects of inhibiting each target on vascular cell function and disease. Enhanced understanding of the molecular mechanisms of vascular side effects of targeted cancer therapy is necessary to effectively manage cancer patients and to design safer targeted cancer therapies for the future.

scholarly journals Rational Design of Potential Bcr-Abl Tyrosine Kinase Inhibitors by the Methods of Molecular Modeling

2020 ◽  
Vol 15 (2) ◽  
pp. 396-415
Author(s):  
A.M. Anrdrianov ◽  
Yu.V. Kornoushenko ◽  
A.D. Karpenko ◽  
I.P. Bosko ◽  
Zh.V. Ignatovich ◽  
...  
Keyword(s):  
Molecular Modeling ◽  
Tyrosine Kinase ◽  
Rational Design ◽  
Kinase Inhibitors ◽  
Calculated Data ◽  
Protein Kinase Inhibitors ◽  
Modeling Tools ◽  
Abl Tyrosine Kinase ◽  
Anti Cancer ◽  
Derivatives Of

Discovery of the nature of inhibiting cancer processes by small organic molecules has changed the principles of the development of drug compounds for antitumor therapy. Recent achievements in this area are associated with the design of small-molecule protein kinase inhibitors, organic compounds exhibiting directed pathogenetic action. In this study, in silico design of 38 potential anti-cancer compounds with multikinase profile was carried out based on the derivatives of 2-arylaminopyrimidine. Evaluation of inhibitory activity potential of these compounds against the native and mutant (T315I) forms of Bcr-Abl tyrosine kinase, an enzyme that plays a key role in the pathogenesis of chronic myeloid leukemia characterized by uncontrolled growth myeloid cells in peripheral blood and bone marrow, was performed using molecular modeling tools. As a result, 5 top-ranking compounds that exhibit, according to the calculated data, a high-affinity binding to the native and mutant Bcr-Abl tyrosine kinase were identified. The designed compounds were shown to form good scaffolds for the development of novel potent antitumor drugs.

scholarly journals A Triple Co-Delivery Liposomal Carrier That Enhances Apoptosis via an Intrinsic Pathway in Melanoma Cells

Cancers ◽  
2019 ◽  
Vol 11 (12) ◽  
pp. 1982 ◽  
Author(s):  
Nina Filipczak ◽  
Anna Jaromin ◽  
Adriana Piwoni ◽  
Mohamed Mahmud ◽  
Can Sarisozen ◽  
...  
Keyword(s):  
Cancer Cells ◽  
Melanoma Cells ◽  
Mitochondrial Pathway ◽  
Cytotoxic Action ◽  
Cancer Therapies ◽  
Normal Cells ◽  
Freeze And Thaw ◽  
Anti Cancer ◽  
Remote Loading ◽  
Activity Mechanism

The effectiveness of existing anti-cancer therapies is based mainly on the stimulation of apoptosis of cancer cells. Most of the existing therapies are somewhat toxic to normal cells. Therefore, the quest for nontoxic, cancer-specific therapies remains. We have demonstrated the ability of liposomes containing anacardic acid, mitoxantrone and ammonium ascorbate to induce the mitochondrial pathway of apoptosis via reactive oxygen species (ROS) production by the killing of cancer cells in monolayer culture and shown its specificity towards melanoma cells. Liposomes were prepared by a lipid hydration, freeze-and-thaw (FAT) procedure and extrusion through polycarbonate filters, a remote loading method was used for dug encapsulation. Following characterization, hemolytic activity, cytotoxicity and apoptosis inducing effects of loaded nanoparticles were investigated. To identify the anticancer activity mechanism of these liposomes, ROS level and caspase 9 activity were measured by fluorescence and by chemiluminescence respectively. We have demonstrated that the developed liposomal formulations produced a high ROS level, enhanced apoptosis and cell death in melanoma cells, but not in normal cells. The proposed mechanism of the cytotoxic action of these liposomes involved specific generation of free radicals by the iron ions mechanism.

scholarly journals mTOR inhibitor everolimus reduces invasiveness of melanoma cells

Human Cell ◽  
2019 ◽  
Vol 33 (1) ◽  
pp. 88-97 ◽  
Author(s):  
Dorota Ciołczyk-Wierzbicka ◽  
Dorota Gil ◽  
Marta Zarzycka ◽  
Piotr Laidler
Keyword(s):  
Mtor Inhibitor ◽  
Kinase Inhibitors ◽  
Mammalian Target Of Rapamycin ◽  
Mek Inhibitor ◽  
Melanoma Cells ◽  
Protein Kinase Inhibitors ◽  
Akt Inhibitor ◽  
Cancer Hallmarks ◽  
Cellular Processes ◽  
Cell Invasiveness

Abstract The mammalian target of rapamycin (mTOR) plays a key role in several cellular processes: proliferation, survival, invasion, and angiogenesis, and therefore, controls cell behavior both in health and in disease. Dysregulation of the mTOR signaling is involved in some of the cancer hallmarks, and thus the mTOR pathway is an important target for the development of a new anticancer therapy. The object of this study is recognition of the possible role of mTOR kinase inhibitors—everolimus single and in combination with selected downstream protein kinases inhibitors: LY294002 (PI3 K), U0126 (ERK1/2), GDC-0879 (B-RAF), AS-703026 (MEK), MK-2206 (AKT), PLX-4032 (B-RRAF) in cell invasion in malignant melanoma. Treatment of melanoma cells with everolimus led to a significant decrease in the level of both phosphorylated: mTOR (Ser2448) and mTOR (Ser2481) as well as their downstream effectors. The use of protein kinase inhibitors produced a significant decrease in metalloproteinases (MMPs) activity, as well as diminished invasion, especially when used in combination. The best results in the inhibition of both MMPs and cell invasiveness were obtained for the combination of an mTOR inhibitor— everolimus with a B-RAF inhibitor—PLX-4032. Slightly less profound reduction of invasiveness was obtained for the combinations of an mTOR inhibitor—everolimus with ERK1/2 inhibitor—U126 or MEK inhibitor—AS-703026 and in the case of MMPs activity decrease for PI3 K inhibitor—LY294002 and AKT inhibitor—MK-2206. The simultaneous use of everolimus or another new generation rapalog with selected inhibitors of crucial signaling kinases seems to be a promising concept in cancer treatment.

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