Pharmacodynamic Effects and Mechanisms of Resistance to Vemurafenib in Patients With Metastatic Melanoma

2013 ◽  
Vol 31 (14) ◽  
pp. 1767-1774 ◽  
Author(s):  
Kerstin Trunzer ◽  
Anna C. Pavlick ◽  
Lynn Schuchter ◽  
Rene Gonzalez ◽  
Grant A. McArthur ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Metastatic Melanoma ◽  
Cell Cycle Progression ◽  
Mapk Pathway ◽  
Objective Response ◽  
Acquired Resistance ◽  
Braf Inhibitor ◽  
Mapk Signaling ◽  
Cycle Progression ◽  
Pharmacodynamic Effects

Purpose To assess pharmacodynamic effects and intrinsic and acquired resistance mechanisms of the BRAF inhibitor vemurafenib in BRAFV600-mutant melanoma, leading to an understanding of the mechanism of action of vemurafenib and ultimately to optimization of metastatic melanoma therapy. Methods In the phase II clinical study NP22657 (BRIM-2), patients received oral doses of vemurafenib (960 mg twice per day). Serial biopsies were collected to study changes in mitogen-activated protein kinase (MAPK) signaling, cell-cycle progression, and factors causing intrinsic or acquired resistance by immunohistochemistry, DNA sequencing, or somatic mutation profiling. Results Vemurafenib inhibited MAPK signaling and cell-cycle progression. An association between the decrease in extracellular signal-related kinase (ERK) phosphorylation and objective response was observed in paired biopsies (n = 22; P = .013). Low expression of phosphatase and tensin homolog showed a modest association with lower response. Baseline mutations in MEK1P124 coexisting with BRAFV600 were noted in seven of 92 samples; their presence did not preclude objective tumor responses. Acquired resistance to vemurafenib associated with reactivation of MAPK signaling as observed by elevated ERK1/2 phosphorylation levels in progressive lesions and the appearance of secondary NRASQ61 mutations or MEK1Q56P or MEK1E203K mutations. These two activating MEK1 mutations had not previously been observed in vivo in biopsies of progressive melanoma tumors. Conclusion Vemurafenib inhibits tumor proliferation and oncogenic BRAF signaling through the MAPK pathway. Acquired resistance results primarily from MAPK reactivation driven by the appearance of secondary mutations in NRAS and MEK1 in subsets of patients. The data suggest that inhibition downstream of BRAF should help to overcome acquired resistance.

scholarly journals Regulation of Raf-1-dependent signaling during early Xenopus development.

1995 ◽  
Vol 15 (12) ◽  
pp. 6686-6693 ◽  
Author(s):  
A M MacNicol ◽  
A J Muslin ◽  
E L Howard ◽  
A Kikuchi ◽  
M C MacNicol ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Embryonic Cell ◽  
Cycle Progression ◽  
Mapk Activity ◽  
Cytostatic Factor ◽  
Differentiation And Proliferation

The Raf-1 gene product is activated in response to cellular stimulation by a variety of growth factors and hormones. Raf-1 activity has been implicated in both cellular differentiation and proliferation. We have examined the regulation of the Raf-1/MEK/MAP kinase (MAPK) pathway during embryonic development in the frog Xenopus laevis. We report that Raf-1, MEK, and MAPK activities are turned off following fertilization and remain undetectable up until blastula stages (stage 8), some 4 h later. Tight regulation of the Raf-1/MEK/MAPK pathway following fertilization is crucial for embryonic cell cycle progression. Inappropriate reactivation of MAPK activity by microinjection of oncogenic Raf-1 RNA results in metaphase cell cycle arrest and, consequently, embryonic lethality. Our findings demonstrate an absolute requirement, in vivo, for inactivation of the MAPK signaling pathway to allow normal cell cycle progression during the period of synchronous cell divisions which occur following fertilization. Further, we show that cytostatic factor effects are mediated through MEK and MAPK.

scholarly journals Whole-genome sequencing of recurrent neuroblastoma reveals somatic mutations that affect key players in cancer progression and telomere maintenance

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Susanne Fransson ◽  
Angela Martinez-Monleon ◽  
Mathias Johansson ◽  
Rose-Marie Sjöberg ◽  
Caroline Björklund ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Whole Genome Sequencing ◽  
Genome Sequencing ◽  
Cancer Progression ◽  
Cell Cycle Progression ◽  
Mapk Signaling ◽  
Telomere Maintenance ◽  
Whole Genome ◽  
Genomic Alterations ◽  
Cycle Progression

AbstractNeuroblastoma is the most common and deadly childhood tumor. Relapsed or refractory neuroblastoma has a very poor prognosis despite recent treatment advances. To investigate genomic alterations associated with relapse and therapy resistance, whole-genome sequencing was performed on diagnostic and relapsed lesions together with constitutional DNA from seven children. Sequencing of relapsed tumors indicates somatic alterations in diverse genes, including those involved in RAS-MAPK signaling, promoting cell cycle progression or function in telomere maintenance and immortalization. Among recurrent alterations, CCND1-gain, TERT-rearrangements, and point mutations in POLR2A, CDK5RAP, and MUC16 were shown in ≥ 2 individuals. Our cohort contained examples of converging genomic alterations in primary-relapse tumor pairs, indicating dependencies related to specific genetic lesions. We also detected rare genetic germline variants in DNA repair genes (e.g., BARD1, BRCA2, CHEK2, and WRN) that might cooperate with somatically acquired variants in these patients with highly aggressive recurrent neuroblastoma. Our data indicate the importance of monitoring recurrent neuroblastoma through sequential genomic characterization and that new therapeutic approaches combining the targeting of MAPK signaling, cell cycle progression, and telomere activity are required for this challenging patient group.

scholarly journals Spirulina Crude Protein Promotes the Migration and Proliferation in IEC-6 Cells by Activating EGFR/MAPK Signaling Pathway

Marine Drugs ◽  
2019 ◽  
Vol 17 (4) ◽  
pp. 205
Author(s):  
Su-Jin Jeong ◽  
Jeong-Wook Choi ◽  
Min-Kyeong Lee ◽  
Youn-Hee Choi ◽  
Taek-Jeong Nam
Keyword(s):  
Cell Cycle ◽  
Epithelial Cells ◽  
Signaling Pathway ◽  
Crude Protein ◽  
Cell Cycle Progression ◽  
Intestinal Epithelial Cells ◽  
Mapk Signaling ◽  
S Phase ◽  
Intestinal Epithelial ◽  
Cycle Progression

Spirulina is a type of filamentous blue-green microalgae known to be rich in nutrients and to have pharmacological effects, but the effect of spirulina on the small intestine epithelium is not well understood. Therefore, this study aims to investigate the proliferative effects of spirulina crude protein (SPCP) on a rat intestinal epithelial cells IEC-6 to elucidate the mechanisms underlying its effect. First, the results of wound-healing and cell viability assays demonstrated that SPCP promoted migration and proliferation in a dose-dependent manner. Subsequently, when the mechanisms of migration and proliferation promotion by SPCP were confirmed, we found that the epidermal growth factor receptor (EGFR) and mitogen-activated protein (MAPK) signaling pathways were activated by phosphorylation. Cell cycle progression from G0/G1 to S phase was also promoted by SPCP through upregulation of the expression levels of cyclins and cyclin-dependent kinases (Cdks), which regulate cell cycle progression to the S phase. Meanwhile, the expression of cyclin-dependent kinase inhibitors (CKIs), such as p21 and p27, decreased with SPCP. In conclusion, our results indicate that activation of EGFR and its downstream signaling pathway by SPCP treatment regulates cell cycle progression. Therefore, these results contribute to the research on the molecular mechanism for SPCP promoting the migration and proliferation of rat intestinal epithelial cells.

scholarly journals Resistance to CDK4/6 Inhibitors in Estrogen Receptor-Positive Breast Cancer

2021 ◽  
Vol 22 (22) ◽  
pp. 12292
Author(s):  
Erin R. Scheidemann ◽  
Ayesha N. Shajahan-Haq
Keyword(s):  
Breast Cancer ◽  
Cell Cycle ◽  
Estrogen Receptor ◽  
Cell Cycle Progression ◽  
Acquired Resistance ◽  
Alternative Methods ◽  
Cycle Progression ◽  
Estrogen Receptor Positive ◽  
New Treatment ◽  
Methods Of Treatment

Estrogen receptor-positive (ER+) breast cancer is the most common form of breast cancer. Antiestrogens were the first therapy aimed at treating this subtype, but resistance to these warranted the development of a new treatment option. CDK4/6 inhibitors address this problem by halting cell cycle progression in ER+ cells, and have proven to be successful in the clinic. Unfortunately, both intrinsic and acquired resistance to CDK4/6 inhibitors are common. Numerous mechanisms of how resistance occurs have been identified to date, including the activation of prominent growth signaling pathways, the loss of tumor-suppressive genes, and noncanonical cell cycle function. Many of these have been successfully targeted and demonstrate the ability to overcome resistance to CDK4/6 inhibitors in preclinical and clinical trials. Future studies should focus on the development of biomarkers so that patients likely to be resistant to CDK4/6 inhibition can initially be given alternative methods of treatment.

scholarly journals Size uniformity of animal cells is actively maintained by a p38 MAPK-dependent regulation of G1-length

2017 ◽  
Author(s):  
Shixuan Liu ◽  
Miriam B. Ginzberg ◽  
Nish Patel ◽  
Marc Hild ◽  
Bosco Leung ◽  
...  
Keyword(s):  
Cell Cycle ◽  
Cell Size ◽  
P38 Mapk ◽  
Cell Cycle Progression ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Small Cells ◽  
Animal Cells ◽  
Cycle Progression ◽  
Size Uniformity

AbstractAnimal cells within a tissue typically display a striking regularity in their size. To date, the molecular mechanisms that control this uniformity are still unknown. We have previously shown that size uniformity in animal cells is promoted, in part, by size-dependent regulation of G1 length. To identify the molecular mechanisms underlying this process, we performed a large-scale small molecule screen and found that the p38 MAPK pathway is involved in coordinating cell size and cell cycle progression. Small cells display higher p38 activity and spend more time in G1 than larger cells. Inhibition of p38 MAPK leads to loss of the compensatory G1 length extension in small cells, resulting in faster proliferation, smaller cell size and increased size heterogeneity. We propose a model wherein the p38 pathway responds to changes in cell size and regulates G1 exit accordingly, to increase cell size uniformity.One-sentence summaryThe p38 MAP kinase pathway coordinates cell growth and cell cycle progression by lengthening G1 in small cells, allowing them more time to grow before their next division.

scholarly journals Cell Cycle Progression in Monkey Cells Expressing Simian Virus 40 Small t Antigen from Adenovirus Vectors

1998 ◽  
Vol 72 (12) ◽  
pp. 9637-9644 ◽  
Author(s):  
Alan K. Howe ◽  
Stéphanie Gaillard ◽  
John S. Bennett ◽  
Kathleen Rundell
Keyword(s):  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Mapk Pathway ◽  
Simian Virus 40 ◽  
Simian Virus ◽  
T Antigen ◽  
Dependent Manner ◽  
Cycle Progression ◽  
Adenovirus Vectors ◽  
Small T Antigen

ABSTRACT The simian virus 40 small t antigen (small-t) is required for optimal viral replication and transformation, especially during the infection of nondividing cells, suggesting that the function of small-t is to promote cell cycle progression. The mechanism through which small-t promotes cell growth reflects, in part, its binding and inhibition of protein phosphatase 2A (PP2A). The use of recombinant adenoviruses allows small-t expression in a majority of cells in a population, thus providing a convenient source of cells for biochemical analyses. In monkey kidney CV1 cells, small-t expressed from these adenovirus vectors activated the mitogen-activated protein kinase (MAPK) pathway, induced JNK activity, and increased AP-1 DNA-binding activity, all in a PP2A-dependent manner. Expression of small-t also caused an increase in the phosphorylation of the Na+/H+ antiporter, a mitogen-activated ion exchanger whose activity correlates with its phosphorylation. At least part of the antiporter phosphorylation induced by small-t reflected activation of the MAPK pathway, as suggested by results of assays using a chemical inhibitor of the MAPK-activating kinase, MEK. Finally, small-t expression from adenovirus vectors promoted efficient cell cycle progression by growth-arrested cells. These vectors should facilitate further analysis of effects of small-t on cell cycle mediators.

scholarly journals LY3214996 relieves acquired resistance to sorafenib in hepatocellular carcinoma cells

2020 ◽  
Author(s):  
Yongfang Ma ◽  
Ruyue Xu ◽  
Xueke Liu ◽  
Yinci Zhang ◽  
Li Song ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Cell Cycle ◽  
Cell Cycle Progression ◽  
Combined Treatment ◽  
Acquired Resistance ◽  
Cycle Progression ◽  
Acquired Drug Resistance ◽  
Anti Cancer ◽  
Apoptotic Effects ◽  
Hcc Cells

Abstract Background: Due to the reactivation of ERK signaling in sorafenib-resisitant hepatocellular carcinoma (HCC) cells, in this study, the anti-cancer effect of LY3214996 (selective ERK1/2 inhibitor) combined with sorafenib on HCC cells was evaluated. Methods: Phosphorylation of the key kinases in the Ras/Raf/MAPK and PI3K/Akt pathways were detected using Western blot. Cells proliferation, migration, cell cycle and apoptosis were evaluated in Huh7 and Huh7 R cells. Results: LY3214996 significantly reduced phosphorylation levels of the tested kinases of Ras/Raf/MAPK and PI3K/Akt pathways including p-c-Raf, p-P90RSK, p-S6K and p-eIF4EBP1 activated by sorafenib, despite increased p-ERK1/2 levels. It was found that LY3214996 enhanced the anti-proliferation, anti-migration, blocking cell cycle progression and pro-apoptotic effects of sorafenib on Huh7 R cells. Conclusions: The reactivation of ERK1/2 might be highly related to molecular mechanism of acquired drug resistance. LY3214996 combined with sorafenib enhanced anti-tumor effects in HCC. Consequently, combined treatment of LY3214996 and sorafenib provides a second-line therapy for acquired resistant in advanced HCC.

Long noncoding RNA CCAT1 promotes cell proliferation and metastasis in human medulloblastoma via MAPK pathway

2018 ◽  
Vol 104 (1) ◽  
pp. 43-50 ◽  
Author(s):  
Ran Gao ◽  
Rui Zhang ◽  
Cuicui Zhang ◽  
Li Zhao ◽  
Yue Zhang
Keyword(s):  
Cell Cycle ◽  
Cell Proliferation ◽  
Cell Lines ◽  
Cell Cycle Progression ◽  
Mapk Pathway ◽  
Cycle Progression ◽  
Medulloblastoma Cell ◽  
Proliferation And Metastasis ◽  
Human Medulloblastoma ◽  
Cell Proliferation And Metastasis

Background: Medulloblastoma is the most common posterior fossa tumor in children and one that easily metastasizes. The mechanisms of how the medulloblastoma develops and progresses remain to be elucidated. The present study aimed to assess the role of long noncoding colon cancer–associated transcript-1 (lncRNA CCAT1) in cell proliferation and metastasis in human medulloblastoma. Methods: Levels of CCAT1 were measured in samples and cell lines of medulloblastoma. Cell cycle progression, cell viability assay, colony formation assay, wound-healing and Transwell assays Corning, Cambridge, MA, USA were used to investigate the viability and motility of cells. Western blot assay was used to investigate the levels of CCAT1 and other proteins. Results: The initial findings indicated that CCAT1 was significantly up-regulated in clinical cancerous tissues and expressed differently in a series of medulloblastoma cell lines. CCAT1 knockdown significantly slowed cell proliferation rates and inhibited cell clonogenic potential in Daoy cells and D283 cells. Cell cycle progression was disrupted with cell proportions in the G0/G1 phase decreased and the proportion in the S phase and G2/M phases increased, in Daoy cells and D283 cells. Concordantly, medulloblastoma tumor cell growth rates were found to be impaired in xenotransplanted mice. After CCAT1 knockdown, cell wound recovery ability was significantly inhibited. Furthermore, the phosphorylated levels of MAPK, ERK and MEK, but not their total levels decreased after the down-regulation of CCAT1 in Daoy and D283 cells. Conclusions: Our results suggested that the lncRNA CCAT1 promotes cell proliferation and metastasis in human medulloblastoma by possibly regulating the MAPK pathway.

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