scholarly journals Targeting the ERK Signaling Pathway in Melanoma

2019 ◽  
Vol 20 (6) ◽  
pp. 1483 ◽  
Author(s):  
Paola Savoia ◽  
Paolo Fava ◽  
Filippo Casoni ◽  
Ottavio Cremona
Keyword(s):  
Drug Resistance ◽  
Signaling Pathway ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Clinical Trial Data ◽  
Resistance Mechanisms ◽  
Additional Advantage ◽  
Activating Mutations ◽  
Extracellular Signal

The discovery of the role of the RAS/RAF/MEK/ERK pathway in melanomagenesis and its progression have opened a new era in the treatment of this tumor. Vemurafenib was the first specific kinase inhibitor approved for therapy of advanced melanomas harboring BRAF-activating mutations, followed by dabrafenib and encorafenib. However, despite the excellent results of first-generation kinase inhibitors in terms of response rate, the average duration of the response was short, due to the onset of genetic and epigenetic resistance mechanisms. The combination therapy with MEK inhibitors is an excellent strategy to circumvent drug resistance, with the additional advantage of reducing side effects due to the paradoxical reactivation of the MAPK pathway. The recent development of RAS and extracellular signal-related kinases (ERK) inhibitors promises to add new players for the ultimate suppression of this signaling pathway and the control of pathway-related drug resistance. In this review, we analyze the pharmacological, preclinical, and clinical trial data of the various MAPK pathway inhibitors, with a keen interest for their clinical applicability in the management of advanced melanoma.

scholarly journals Primary cilia mediate diverse kinase inhibitor resistance mechanisms in cancer

2017 ◽  
Author(s):  
Andrew D. Jenks ◽  
Simon Vyse ◽  
Jocelyn P. Wong ◽  
Deborah Keller ◽  
Tom Burgoyne ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Primary Cilia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Human Cancer ◽  
Structural Features ◽  
Resistance Mechanisms ◽  
Pathway Activation ◽  
Inhibitor Resistance

AbstractPrimary cilia are microtubule-based organelles that detect mechanical and chemical stimuli. Although cilia house a number of oncogenic molecules (including Smoothened, KRAS, EGFR, and PDGFR), their precise role in cancer remains unclear. We have interrogated the role of cilia in acquired andde novoresistance to a variety of kinase inhibitors, and found that in several examples, resistant cells are distinctly characterized by an increase in the number and/or length of cilia with altered structural features. Changes in cilia length seem to be linked to the lack of recruitment of Kif7 and IFT81 to cilia tips, and result in enhanced hedgehog pathway activation. Notably, Kif7 knockdown is sufficient to confer drug resistance in drug sensitive cells. Conversely, targeting of cilia length or integrity through genetic and pharmacological approaches overcomes kinase inhibitor resistance. The identification of a broad mechanism of pathway-unbiased drug resistance, represents a major advancement in oncology, and helps define a specific and important role for cilia in human cancer.

scholarly journals Exploiting vulnerabilities in cancer signalling networks to combat targeted therapy resistance

2018 ◽  
Vol 62 (4) ◽  
pp. 583-593 ◽  
Author(s):  
Peter T. Harrison ◽  
Paul H. Huang
Keyword(s):  
Drug Resistance ◽  
Targeted Therapy ◽  
Kinase Inhibitors ◽  
Effective Means ◽  
Deep Understanding ◽  
Therapy Resistance ◽  
Resistance Mechanisms ◽  
Precision Oncology ◽  
First Line ◽  
Clinical Responses

Drug resistance remains one of the greatest challenges facing precision oncology today. Despite the vast array of resistance mechanisms that cancer cells employ to subvert the effects of targeted therapy, a deep understanding of cancer signalling networks has led to the development of novel strategies to tackle resistance both in the first-line and salvage therapy settings. In this review, we provide a brief overview of the major classes of resistance mechanisms to targeted therapy, including signalling reprogramming and tumour evolution; our discussion also focuses on the use of different forms of polytherapies (such as inhibitor combinations, multi-target kinase inhibitors and HSP90 inhibitors) as a means of combating resistance. The promise and challenges facing each of these polytherapies are elaborated with a perspective on how to effectively deploy such therapies in patients. We highlight efforts to harness computational approaches to predict effective polytherapies and the emerging view that exceptional responders may hold the key to better understanding drug resistance. This review underscores the importance of polytherapies as an effective means of targeting resistance signalling networks and achieving durable clinical responses in the era of personalised cancer medicine.

scholarly journals Multiple distinct pathways lead to hyperubiquitylated insoluble TDP-43 protein independent of its translocation into stress granules

2019 ◽  
Vol 295 (3) ◽  
pp. 673-689 ◽  
Author(s):  
Friederike Hans ◽  
Hanna Glasebach ◽  
Philipp J. Kahle
Keyword(s):  
Oxidative Stress ◽  
Protein Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Glycogen Synthase ◽  
Osmotic Shock ◽  
Protein Kinase R ◽  
Extracellular Signal ◽  
Rapid Dissolution ◽  
The Central Nervous System

Insoluble, hyperubiquitylated TAR DNA-binding protein of 43 kDa (TDP-43) in the central nervous system characterizes frontotemporal dementia and ALS in many individuals with these neurodegenerative diseases. The causes for neuropathological TDP-43 aggregation are unknown, but it has been suggested that stress granule (SG) formation is important in this process. Indeed, in human embryonic kidney HEK293E cells, various SG-forming conditions induced very strong TDP-43 ubiquitylation, insolubility, and reduced splicing activity. Osmotic stress–induced SG formation and TDP-43 ubiquitylation occurred rapidly and coincided with colocalization of TDP-43 and SG markers. Washout experiments confirmed the rapid dissolution of SGs, accompanied by normalization of TDP-43 ubiquitylation and solubility. Surprisingly, interference with the SG process using a protein kinase R–like endoplasmic reticulum kinase inhibitor (GSK2606414) or the translation blocker emetine did not prevent TDP-43 ubiquitylation and insolubility. Thus, parallel pathways may lead to pathological TDP-43 modifications independent of SG formation. Using a panel of kinase inhibitors targeting signaling pathways of the osmotic shock inducer sorbitol, we could largely rule out the stress-activated and extracellular signal–regulated protein kinase modules and glycogen synthase kinase 3β. For arsenite, but not for sorbitol, quenching oxidative stress with N-acetylcysteine did suppress both SG formation and TDP-43 ubiquitylation and insolubility. Thus, sodium arsenite appears to promote SG formation and TDP-43 modifications via oxidative stress, but sorbitol stimulates TDP-43 ubiquitylation and insolubility via a novel pathway(s) independent of SG formation. In conclusion, pathological TDP-43 modifications can be mediated via multiple distinct pathways for which SGs are not essential.

A phase I, pharmacokinetic and pharmacodynamic study of sorafenib (S), a multi-targeted kinase inhibitor in combination with temsirolimus (T), an mTOR inhibitor in patients with advanced solid malignancies

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 3512-3512 ◽  
Author(s):  
A. Patnaik ◽  
A. Ricart ◽  
J. Cooper ◽  
K. Papadopoulos ◽  
M. Beeram ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Single Agent ◽  
Resistance Mechanisms ◽  
Survival Pathway ◽  
Solid Malignancies ◽  
Hand Foot Syndrome ◽  
Grade 3 ◽  
Pathway Inhibition ◽  
Oral Doses

3512 Background: The combination of S and T is hypothesized to maximize pathway inhibition by concurrently targeting parallel signaling mechanisms and will abrogate potential resistance mechanisms directed towards the MAPK pathway through increased signaling via the survival pathway involving PI3K/Akt. Methods: Eligible patients (pts) were treated with escalating continuous oral doses of S (200 and 400 mg BID) and weekly T IV (15 mg, 25 mg). S began on day 8 of course 1 to permit PK evaluations of T. PD studies in PBMCs were performed serially in pts. Results: To date, 24 evaluable pts have received 85 courses [median 3;range1–12] in the following S/T dose cohorts; cohort 1: 200 mg/15 mg (n=6), cohort 2: 400 mg/15 mg (n=11), cohort 3: 400 mg/25 mg (n=6), and cohort 4: 200 mg/25 mg (n=1). Patients demographics were males/female 11/13, median age 54.5 [range 27–71] and PS of 0/1/2 : n=9/13/2. Dose limiting toxicities (DLT) were grade 3 typhlitis in 1/6 pts in cohort 1, and mucositis in 1/6 pts in cohort 2. Expansion of cohort 2 to 11 patients resulted in 4 additional DLTs (hand foot syndrome (HFS) x 2 pts, thrombycytopenia/rash x 1 pt, creatinine elevation x 1 pt). 3 of 6 pts in cohort 3 experienced DLT (HFS x 2 pts, thrombocytopenia x 1 pt). PK analyses show no evidence of S effect on T kinetics while Css,min values of S are consistent with those reported in single-agent studies (S 200mg BID median Css,min 4.42 μg/mL [SD 3.05], S 400 mg BID median Css,min 5.11 μg/mL [SD 4.35]). Apparent downregulation of 4E-BP1 and activated forms of p70S6 kinase and ERK was observed in some patients following treatment. Partial responses have occurred in NHL (1 pt) and papillary thyroid cancer (1 pt) and prolonged SD (> 12 mo) has been observed in RCC (1 pt). Conclusions: The combination of S and T demonstrate significant mucocutaneous toxicity at full doses of S, however preliminary PK analyses show no evidence of drug-drug interactions. Characterization of an intermediate dose of S 200 mg BID/T 25 mg IV is ongoing. [Table: see text]

Pharmacological interactions of TKIs with the P-gp drug transport protein.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2536-2536 ◽  
Author(s):  
Sandra Roche ◽  
Kasper Pedersen ◽  
Grainne Dunne ◽  
Denis Collins ◽  
Aoife Devery ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Drug Transport ◽  
Kinase Inhibitors ◽  
Resistance Mechanisms ◽  
Cancer Drug ◽  
Clear Understanding ◽  
Pharmacological Interactions

2536 Background: Tyrosine Kinase Inhibitors (TKIs) can interact with drug transport proteins. P-gp is a transporter with two important roles in cancer drug therapy. If overexpressed in tumour cells it can cause drug resistance. However, P-gp, expressed in tissues as part of normal drug clearance mechanisms, is also involved in termination of drug action. Hence, TKI-mediated interactions with P-gp have significant therapeutic consequences. Methods: P-gp over-expressing cancer cell lines were used to determine the inhibitor or substrate status of tyrosine kinase inhibitors (erlotinib, gefitinib, lapatinib, dasatinb, neratinib, afatinib and pazopanib). Cell proliferation assays in combination with a potent P-gp inhibitor, or P-gp substrate were also employed. Findings were augmented using LC-MS-based quantitation of cellular levels of target drugs. Results: We summarise our findings of four distinct interactions with P-gp among various TKIs. Some agents have little interaction at conventional doses; others can act as P-gp inhibitors without being substrates; substrates without being inhibitors or substrates which also prevent the actions of the transporter.Eachof the investigated TKIs has a distinct relationship with P-gp. As examples, lapatinib is an inhibitor but not a substrate, dasatinib is a substrate but not an inhibitor, while pazopanib has little interaction with P-gp. Other agents also have an effect on or are affected by P-gp to varying amounts with some of these interactions likely to be suprapharmacological. Conclusions: P-gp protein has important roles both in resistance and drug toxicology, hence, a clear understanding of the interaction of emerging drugs with this transporter is vital. Agents which are inhibitors of P-gp may have applications in drug resistance circumvention but may also greatly exacerbate the toxicity of concurrently administered P-gp substrate cytotoxics; conversely the activity of P-gp substrate TKIs may be reduced by tumour overexpression of the transporter. Hence in vitro screening of TKI-transporter interactions may identify putative TKI resistance mechanisms, help guide the development of combination schedule trials and/or reducing unwanted treatment side effects.

scholarly journals Identification of RAS-Mitogen-Activated Protein Kinase Signaling Pathway Modulators in an ERF1 Redistribution® Screen

2006 ◽  
Vol 11 (4) ◽  
pp. 423-434 ◽  
Author(s):  
Charlotta Grånäs ◽  
Betina Kerstin Lundholt ◽  
Frosty Loechel ◽  
Hans-Christian Pedersen ◽  
Sara Petersen Bjørn ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitors ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
A Cell ◽  
Protein Kinase Signaling

The RAS-mitogen-activated protein kinase (MAPK) signaling pathway has a central role in regulating the proliferation and survival of both normal and tumor cells. This pathway has been 1 focus area for the development of anticancer drugs, resulting in several compounds, primarily kinase inhibitors, in clinical testing. The authors have undertaken a cell-based, high-throughput screen using a novel ERF1 Redistribution® assay to identify compounds that modulate the signaling pathway. The hit compounds were subsequently tested for activity in a functional cell proliferation assay designed to selectively detect compounds inhibiting the proliferation of MAPK pathway-dependent cancer cells. The authors report the identification of 2 cell membrane-permeable compounds that exhibit activity in the ERF1 Redistribution® assay and selectively inhibit proliferation of MAPK pathway-dependent malignant melanoma cells at similar potencies (IC50 =< 5 μM). These compounds have drug-like structures and are negative in RAF, MEK, and ERK in vitro kinase assays. Drugs belonging to these compound classes may prove useful for treating cancers caused by excessive MAPK pathway signaling. The results also show that cell-based, high-content Redistribution® screens can detect compounds with different modes of action and reveal novel targets in a pathway known to be disease relevant.

scholarly journals Isopanduratin A Inhibits Tumor Necrosis Factor (TNF)-α-Induced Nuclear Factor κB Signaling Pathway by Promoting Extracellular Signal-Regulated Kinase-Dependent Ectodomain Shedding of TNF Receptor 1 in Human Lung Adenocarcinoma A549 Cells

BioChem ◽  
2021 ◽  
Vol 1 (3) ◽  
pp. 174-189
Author(s):  
Chihiro Moriwaki ◽  
Riho Tanigaki ◽  
Yasunobu Miyake ◽  
Nghia Trong Vo ◽  
Mai Thanh Thi Nguyen ◽  
...  
Keyword(s):  
Map Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
A549 Cells ◽  
Nuclear Factor Κb ◽  
P38 Map Kinase ◽  
Ectodomain Shedding ◽  
Extracellular Signal ◽  
Tnf Α ◽  
Lung Adenocarcinoma A549

Tumor necrosis factor α (TNF-α) induces the nuclear factor κB (NF-κB) signaling pathway via TNF receptor 1 (TNF-R1). We recently reported that isopanduratin A inhibited the TNF-α-induced NF-κB signaling pathway in human lung adenocarcinoma A549 cells. In the present study, we found that isopanduratin A did not inhibit the interleukin-1α-induced NF-κB signaling pathway in A549 cells. Isopanduratin A down-regulated the expression of TNF-R1 in these cells. We also revealed that isopanduratin A down-regulated the cell surface expression of TNF-R1 by promoting the cleavage of TNF-R1 into its soluble forms. TAPI-2, an inhibitor of TNF-α-converting enzyme, suppressed the inhibitory activity of isopanduratin A against the TNF-α-induced activation of NF-κB. The mitogen-activated protein (MAP) kinase/extracellular signal-regulated kinase (ERK) kinase inhibitor U0126, but not the p38 MAP kinase inhibitor SB203580, blocked the ectodomain shedding of TNF-R1 induced by isopanduratin A. Consistent with this result, isopanduratin A induced the rapid phosphorylation of ERK, but not p38 MAP kinase. Isopanduratin A also promoted the phosphorylation of eukaryotic initiation factor 2α (eIF2α). The present results indicate that isopanduratin A inhibits TNF-α-induced NF-κB signaling pathway by promoting ERK-dependent ectodomain shedding of cell surface TNF-R1, and also decreases cellular TNF-R1 levels through the phosphorylation of eIF2α in A549 cells.

scholarly journals A screen for combination therapies inBRAF/NRASwild type melanoma identifies nilotinib plus MEK inhibitor as a synergistic combination

2017 ◽  
Author(s):  
Marco Ranzani ◽  
Kristel Kemper ◽  
Magali Michaut ◽  
Oscar Krijgsman ◽  
Nanne Aben ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Mapk Pathway ◽  
Acquired Resistance ◽  
Mek Inhibitor ◽  
Resistance Mechanisms ◽  
Wild Type ◽  
Genome Wide ◽  
Melanoma Patients ◽  
Inhibitor Combination

AbstractDespite recent therapeutic advances in the management ofBRAFV600-mutant melanoma, there is still a compelling need for more effective treatments for patients who developedBRAF/NRASwild type disease. Since the activity of single targeted agents is limited by innate and acquired resistance, we performed a high-throughput drug screen using 180 drug combinations to generate over 18,000 viability curves, with the aim of identifying agents that synergise to killBRAF/NRASwild type melanoma cells. From this screen we observed strong synergy between the tyrosine kinase inhibitor nilotinib and MEK inhibitors and validated this combination in an independent cell line collection. We found that AXL expression was associated with synergy to the nilotinib/MEK inhibitor combination, and that both drugs work in concert to suppress pERK. This finding was supported by genome-wide CRISPR screening which revealed that resistance mechanisms converge on regulators of the MAPK pathway. Finally, we validated the synergy of nilotinib/trametinib combinationin vivousing patient-derived xenografts. Our results indicate that a nilotinib/MEK inhibitor combination may represent an effective therapy inBRAF/NRASwild type melanoma patients.

scholarly journals LY294002 Is a Promising Inhibitor to Overcome Sorafenib Resistance in FLT3-ITD Mutant AML Cells by Interfering With PI3K/Akt Signaling Pathway

2021 ◽  
Vol 11 ◽  
Author(s):  
Amin Huang ◽  
Peiting Zeng ◽  
Yinguang Li ◽  
Wenhua Lu ◽  
Yaoming Lai
Keyword(s):  
Drug Resistance ◽  
Tyrosine Kinase ◽  
Signaling Pathway ◽  
Kinase Inhibitor ◽  
Response Duration ◽  
Akt Signaling ◽  
Clinical Activity ◽  
Akt Signaling Pathway ◽  
Atp Production ◽  
Pi3k Inhibitor Ly294002

Internal tandem duplications (ITD) mutation within FMS-like tyrosine kinase 3 (FLT3), the most frequent mutation happens in almost 20% acute myeloid leukemia (AML) patients, always predicts a poor prognosis. As a small molecule tyrosine kinase inhibitor, sorafenib is clinically used for the treatment of advanced renal cell carcinoma (RCC), hepatocellular carcinoma (HCC), and differentiated thyroid cancer (DTC), with its preclinical and clinical activity demonstrated in the treatment of Fms-like tyrosine kinase 3-internal tandem duplication (FLT3-ITD) mutant AML. Even though it shows a rosy future in the AML treatment, the short response duration remains a vital problem that leads to treatment failure. Rapid onset of drug resistance is still a thorny problem that we cannot overlook. Although the mechanisms of drug resistance have been studied extensively in the past years, there is still no consensus on the exact reason for resistance and without effective therapeutic regimens established clinically. My previous work reported that sorafenib-resistant FLT3-ITD mutant AML cells displayed mitochondria dysfunction, which rendered cells depending on glycolysis for energy supply. In my present one, we further illustrated that losing the target protein FLT3 and the continuously activated PI3K/Akt signaling pathway may be the reason for drug resistance, with sustained activation of PI3K/AKT signaling responsible for the highly glycolytic activity and adenosine triphosphate (ATP) generation. PI3K inhibitor, LY294002, can block PI3K/AKT signaling, further inhibit glycolysis to disturb ATP production, and finally induce cell apoptosis. This finding would pave the way to remedy the FLT3-ITD mutant AML patients who failed with FLT3 targeted therapy.

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