scholarly journals An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

2017 ◽  
Vol 214 (6) ◽  
pp. 1691-1710 ◽  
Author(s):  
Helen L. Young ◽  
Emily J. Rowling ◽  
Mattia Bugatti ◽  
Emanuele Giurisato ◽  
Nadia Luheshi ◽  
...  
Keyword(s):  
Mapk Pathway ◽  
Acquired Resistance ◽  
Drug Tolerance ◽  
Mapk Signaling ◽  
Signaling Network ◽  
Mitogen Activated Protein Kinase ◽  
Cytokine Signaling ◽  
Adaptive Responses ◽  
Mapk Inhibitors

Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatment.

scholarly journals Extracellular Signal-Regulated Kinase 2 Interacts with and Is Negatively Regulated by the LIM-Only Protein FHL2 in Cardiomyocytes

2004 ◽  
Vol 24 (3) ◽  
pp. 1081-1095 ◽  
Author(s):  
Nicole H. Purcell ◽  
Dina Darwis ◽  
Orlando F. Bueno ◽  
Judith M. Müller ◽  
Roland Schüle ◽  
...  
Keyword(s):  
Mammalian Cells ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Interacting Protein ◽  
Hypertrophic Response ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

ABSTRACT The mitogen-activated protein kinase (MAPK) signaling pathway regulates diverse biologic functions including cell growth, differentiation, proliferation, and apoptosis. The extracellular signal-regulated kinases (ERKs) constitute one branch of the MAPK pathway that has been implicated in the regulation of cardiac differentiated growth, although the downstream mechanisms whereby ERK signaling affects this process are not well characterized. Here we performed a yeast two-hybrid screen with ERK2 bait and a cardiac cDNA library to identify novel proteins involved in regulating ERK signaling in cardiomyocytes. This screen identified the LIM-only factor FHL2 as an ERK interacting protein in both yeast and mammalian cells. In vivo, FHL2 and ERK2 colocalized in the cytoplasm at the level of the Z-line, and interestingly, FHL2 interacted more efficiently with the activated form of ERK2 than with the dephosphorylated form. ERK2 also interacted with FHL1 and FHL3 but not with the muscle LIM protein. Moreover, at least two LIM domains in FHL2 were required to mediate efficient interaction with ERK2. The interaction between ERK2 and FHL2 did not influence ERK1/2 activation, nor was FHL2 directly phosphorylated by ERK2. However, FHL2 inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter. Finally, FHL2 partially antagonized the cardiac hypertrophic response induced by activated MEK-1, GATA4, and phenylephrine agonist stimulation. Collectively, these results suggest that FHL2 serves a repressor function in cardiomyocytes through its ability to inhibit ERK1/2 transcriptional coupling.

scholarly journals MEK-inhibitor-mediated rescue of skeletal myopathy caused by activating Hras mutation in a Costello syndrome mouse model

2021 ◽  
Author(s):  
William E. Tidyman ◽  
Alice F. Goodwin ◽  
Yoshiko Maeda ◽  
Ophir D. Klein ◽  
Katherine A. Rauen
Keyword(s):  
Mouse Model ◽  
Mapk Pathway ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Costello Syndrome ◽  
Skeletal Myopathy ◽  
Mitogen Activated Protein

Costello syndrome (CS) is a congenital disorder caused by heterozygous activating germline HRAS mutations in the canonical Ras/mitogen-activated protein kinase (Ras/MAPK) pathway. CS is one of the RASopathies, a large group of syndromes due to mutations within various components of the Ras/MAPK pathway. An important part of the phenotype that greatly impacts quality of life is hypotonia. To gain a better understanding of the mechanisms underlying hypotonia in CS, a mouse model with an activating HrasG12V allele was utilized. We identified a skeletal myopathy that was due in part to an inhibition of embryonic myogenesis and myofiber formation, resulting in a reduction of myofiber size and number that led to reduced muscle mass and strength. In addition to hyperactivation of the Ras/MAPK and PI3K/AKT pathways, there was a significant reduction of p38 signaling, as well as global transcriptional alterations consistent with the myopathic phenotype. Inhibition of Ras/MAPK pathway signaling using a MEK inhibitor rescued the HrasG12V myopathy phenotype both in vitro and in vivo, demonstrating that increased MAPK signaling is the main cause of the muscle phenotype in CS.

scholarly journals Spa2p Interacts with Cell Polarity Proteins and Signaling Components Involved in Yeast Cell Morphogenesis

1998 ◽  
Vol 18 (7) ◽  
pp. 4053-4069 ◽  
Author(s):  
Yi-Jun Sheu ◽  
Beatriz Santos ◽  
Nathalie Fortin ◽  
Christine Costigan ◽  
Michael Snyder
Keyword(s):  
Actin Cytoskeleton ◽  
Hybrid System ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Velocity Sedimentation ◽  
Mitogen Activated Protein ◽  
Multiple Regions ◽  
Two Hybrid

ABSTRACT The yeast protein Spa2p localizes to growth sites and is important for polarized morphogenesis during budding, mating, and pseudohyphal growth. To better understand the role of Spa2p in polarized growth, we analyzed regions of the protein important for its function and proteins that interact with Spa2p. Spa2p interacts with Pea2p and Bud6p (Aip3p) as determined by the two-hybrid system; all of these proteins exhibit similar localization patterns, and spa2Δ,pea2Δ, and bud6Δ mutants display similar phenotypes, suggesting that these three proteins are involved in the same biological processes. Coimmunoprecipitation experiments demonstrate that Spa2p and Pea2p are tightly associated with each other in vivo. Velocity sedimentation experiments suggest that a significant portion of Spa2p, Pea2p, and Bud6p cosediment, raising the possibility that these proteins form a large, 12S multiprotein complex. Bud6p has been shown previously to interact with actin, suggesting that the 12S complex functions to regulate the actin cytoskeleton. Deletion analysis revealed that multiple regions of Spa2p are involved in its localization to growth sites. One of the regions involved in Spa2p stability and localization interacts with Pea2p; this region contains a conserved domain, SHD-II. Although a portion of Spa2p is sufficient for localization of itself and Pea2p to growth sites, only the full-length protein is capable of complementing spa2 mutant defects, suggesting that other regions are required for Spa2p function. By using the two-hybrid system, Spa2p and Bud6p were also found to interact with components of two mitogen-activated protein kinase (MAPK) pathways important for polarized cell growth. Spa2p interacts with Ste11p (MAPK kinase [MEK] kinase) and Ste7p (MEK) of the mating signaling pathway as well as with the MEKs Mkk1p and Mkk2p of the Slt2p (Mpk1p) MAPK pathway; for both Mkk1p and Ste7p, the Spa2p-interacting region was mapped to the N-terminal putative regulatory domain. Bud6p interacts with Ste11p. The MEK-interacting region of Spa2p corresponds to the highly conserved SHD-I domain, which is shown to be important for mating and MAPK signaling. spa2 mutants exhibit reduced levels of pheromone signaling and an elevated level of Slt2p kinase activity. We thus propose that Spa2p, Pea2p, and Bud6p function together, perhaps as a complex, to promote polarized morphogenesis through regulation of the actin cytoskeleton and signaling pathways.

scholarly journals The p38 MAPK Signaling Activation in Colorectal Cancer upon Therapeutic Treatments

2020 ◽  
Vol 21 (8) ◽  
pp. 2773 ◽  
Author(s):  
Angelina Pranteda ◽  
Valentina Piastra ◽  
Lorenzo Stramucci ◽  
Deborah Fratantonio ◽  
Gianluca Bossi
Keyword(s):  
Colorectal Carcinoma ◽  
P38 Mapk ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Chemotherapeutic Agents ◽  
Mitogen Activated Protein Kinase ◽  
High Expectations ◽  
P38 Mapk Pathway ◽  
Mapk Inhibitors ◽  
Signaling Activation

Pharmacological treatment of colorectal carcinoma currently proceeds through the administration of a combination of different chemotherapeutic agents. In the case of rectal carcinoma, radiation therapy also represents a therapeutic strategy. In an attempt at translating much-needed new targeted therapy to the clinics, p38 mitogen activated protein kinase (MAPK) inhibitors have been tested in clinical trials involving colorectal carcinoma patients, especially in combination with chemotherapy; however, despite the high expectations raised by a clear involvement of the p38 MAPK pathway in the response to therapeutic treatments, poor results have been obtained so far. In this work, we review recent insights into the exact role of the p38 MAPK pathway in response to currently available therapies for colorectal carcinoma, depicting an intricate scenario in which the p38 MAPK node presents many opportunities, as well as many challenges, for its perspective exploitation for clinical purposes.

Effects of Molecular Heterogeneity on Survival of Patients With BRAFV600-Mutated Melanoma Treated With Vemurafenib With or Without Cobimetinib in the coBRIM Study

2018 ◽  
pp. 1-18 ◽  
Author(s):  
Matthew J. Wongchenko ◽  
Antoni Ribas ◽  
Paolo A. Ascierto ◽  
Brigitte Dréno ◽  
Anna Maria di Giacomo ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Proportional Hazards ◽  
Mapk Pathway ◽  
Acquired Resistance ◽  
Mapk Signaling ◽  
Cox Proportional Hazards ◽  
Mitogen Activated Protein Kinase ◽  
Phase Iii ◽  
Molecular Heterogeneity ◽  
Proliferation Markers

Purpose The treatment of advanced BRAFV600-mutated melanomas with BRAF inhibitors (BRAFi) has improved survival, but the efficacy of BRAFi varies among individuals and the development of acquired resistance to BRAFi through reactivation of mitogen-activated protein kinase (MAPK) signaling is common. We performed an exploratory, retrospective analysis to investigate the effects of BRAFV600 allelic balance, coexisting oncogene mutations, cell proliferation signaling levels, and loss of PTEN expression on progression-free survival (PFS) in patients in the phase III coBRIM study, which compared the combination of the MEK inhibitor cobimetinib with the BRAFi vemurafenib versus vemurafenib as monotherapy. Methods Baseline tumor samples from the intention-to-treat population were analyzed by targeted deep sequencing at a median coverage of 3,600× and by immunohistochemistry for cell proliferation markers, BRAFV600E, and PTEN. The association of these biomarkers with PFS was assessed by Cox proportional hazards modeling. Gene expression in relation to loss of PTEN was profiled by RNA sequencing in 205 patient samples and 42 BRAFV600-mutated melanoma cell lines. Results Neither BRAFV600 allelic balance nor coexisting mutations in the RAS/RAF/RTK pathway affected PFS in either treatment group. Increased baseline MAPK signaling and cell proliferation did not affect PFS in patients treated with cobimetinib combined with vemurafenib. PTEN loss was associated with reduced PFS in patients treated with vemurafenib alone but not in patients treated with cobimetinib combined with vemurafenib. Conclusion Deeper inhibition of the MAPK pathway through targeting of both MEK and BRAF may override the effects of tumor heterogeneity and improve PFS in all patients with advanced BRAFV600 melanoma.

scholarly journals A Comprehensive Review on MAPK: A Promising Therapeutic Target in Cancer

Cancers ◽  
2019 ◽  
Vol 11 (10) ◽  
pp. 1618 ◽  
Author(s):  
Braicu ◽  
Buse ◽  
Busuioc ◽  
Drula ◽  
Gulei ◽  
...  
Keyword(s):  
Cancer Therapy ◽  
Mapk Pathway ◽  
Alternative Pathway ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
Cancer Management ◽  
Pathway Activation ◽  
Promising Therapeutic Target ◽  
Mitogen Activated Protein ◽  
Mapk Inhibitors

The mitogen-activated protein kinase (MAPK) pathway is an important bridge in the switch from extracellular signals to intracellular responses. Alterations of signaling cascades are found in various diseases, including cancer, as a result of genetic and epigenetic changes. Numerous studies focused on both the homeostatic and the pathologic conduct of MAPK signaling; however, there is still much to be deciphered in terms of regulation and action models in both preclinical and clinical research. MAPK has implications in the response to cancer therapy, particularly the activation of the compensatory pathways in response to experimental MAPK inhibition. The present paper discusses new insights into MAPK as a complex cell signaling pathway with roles in the sustenance of cellular normal conduit, response to cancer therapy, and activation of compensatory pathways. Unfortunately, most MAPK inhibitors trigger resistance due to the activation of compensatory feed-back loops in tumor cells and tumor microenvironment components. Therefore, novel combinatorial therapies have to be implemented for cancer management in order to restrict the possibility of alternative pathway activation, as a perspective for developing novel therapies based on integration in translational studies.

scholarly journals Exploiting codon usage identifies RpS21 as an in vivo signal strength-dependent Ras/MAPK regulator

2019 ◽  
Author(s):  
Jessica K. Sawyer ◽  
Zahra Kabiri ◽  
Ruth A. Montague ◽  
Sarah V. Paramore ◽  
Erez Cohen ◽  
...  
Keyword(s):  
Codon Usage ◽  
Mapk Pathway ◽  
Mapk Signaling ◽  
Ribosomal Gene ◽  
Mitogen Activated Protein Kinase ◽  
Biological Processes ◽  
Cell Tissue ◽  
Mitogen Activated Protein ◽  
Multiple Cell

ABSTRACTSignal transduction pathways are intricately fine-tuned to accomplish diverse biological processes. An example is the conserved Ras/mitogen-activated-protein-kinase (MAPK) pathway, which exhibits context-dependent signaling output dynamics and regulation. Here, by altering codon usage as a novel platform to control signaling output, we screened the Drosophila genome for modifiers specific to either weak or strong Ras-driven eye phenotypes. We mapped the underlying gene from one modifier to the ribosomal gene RpS21. RpS21 preferentially influences weak Ras/MAPK signaling outputs, and negatively regulates Ras/MAPK in multiple cell/tissue and signaling settings. In turn, MAPK signaling may regulate its own negative feedback by promoting RpS21 expression. These data show that codon usage manipulation can identify output-specific signaling regulators, and identify RpS21 as an in vivo Ras/MAPK phenotypic regulator.

scholarly journals Combined VEGFR and MAPK pathway inhibition in angiosarcoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Michael J. Wagner ◽  
Yasmin A. Lyons ◽  
Jean H. Siedel ◽  
Robert Dood ◽  
Archana S. Nagaraja ◽  
...  
Keyword(s):  
Protein Kinase ◽  
Mapk Pathway ◽  
Combined Treatment ◽  
Mek Inhibitor ◽  
Mapk Signaling ◽  
Mitogen Activated Protein Kinase ◽  
In Vivo Model ◽  
Mitogen Activated Protein

AbstractAngiosarcoma is an aggressive malignancy of endothelial cells that carries a high mortality rate. Cytotoxic chemotherapy can elicit clinical responses, but the duration of response is limited. Sequencing reveals multiple mutations in angiogenesis pathways in angiosarcomas, particularly in vascular endothelial growth factor (VEGFR) and mitogen-activated protein kinase (MAPK) signaling. We aimed to determine the biological relevance of these pathways in angiosarcoma. Tissue microarray consisting of clinical formalin-fixed paraffin embedded tissue archival samples were stained for phospho- extracellular signal-regulated kinase (p-ERK) with immunohistochemistry. Angiosarcoma cell lines were treated with the mitogen-activated protein kinase kinase (MEK) inhibitor trametinib, pan-VEGFR inhibitor cediranib, or combined trametinib and cediranib and viability was assessed. Reverse phase protein array (RPPA) was performed to assess multiple oncogenic protein pathways. SVR angiosarcoma cells were grown in vivo and gene expression effects of treatment were assessed with whole exome RNA sequencing. MAPK signaling was found active in over half of clinical angiosarcoma samples. Inhibition of MAPK signaling with the MEK inhibitor trametinib decreased the viability of angiosarcoma cells. Combined inhibition of the VEGF and MAPK pathways with cediranib and trametinib had an additive effect in in vitro models, and a combinatorial effect in an in vivo model. Combined treatment led to smaller tumors than treatment with either agent alone. RNA-seq demonstrated distinct expression signatures between the trametinib treated tumors and those treated with both trametinib and cediranib. These results indicate a clinical study of combined VEGFR and MEK inhibition in angiosarcoma is warranted.

scholarly journals Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression

2019 ◽  
Vol 38 (1) ◽  
Author(s):  
S. Napolitano ◽  
N. Matrone ◽  
A. L. Muddassir ◽  
G. Martini ◽  
A. Sorokin ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Molecular Mechanisms ◽  
Mapk Pathway ◽  
Combined Treatment ◽  
Acquired Resistance ◽  
Mek Inhibitor ◽  
Gene Signature ◽  
Mapk Signaling

Abstract Background Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. Methods We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. Results The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. Conclusions These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.

scholarly journals KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Elsa B Krall ◽  
Belinda Wang ◽  
Diana M Munoz ◽  
Nina Ilic ◽  
Srivatsan Raghavan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Mapk Pathway ◽  
Cell Metabolism ◽  
Acquired Resistance ◽  
Mapk Signaling ◽  
Negative Regulator ◽  
Mitogen Activated Protein Kinase ◽  
Mitogen Activated Protein ◽  
Clinical Responses ◽  
Altered Cell

Inhibitors that target the receptor tyrosine kinase (RTK)/Ras/mitogen-activated protein kinase (MAPK) pathway have led to clinical responses in lung and other cancers, but some patients fail to respond and in those that do resistance inevitably occurs (<xref ref-type="bibr" rid="bib2">Balak et al., 2006</xref>; <xref ref-type="bibr" rid="bib30">Kosaka et al., 2006</xref>; <xref ref-type="bibr" rid="bib37">Rudin et al., 2013</xref>; <xref ref-type="bibr" rid="bib45">Wagle et al., 2011</xref>). To understand intrinsic and acquired resistance to inhibition of MAPK signaling, we performed CRISPR-Cas9 gene deletion screens in the setting of BRAF, MEK, EGFR, and ALK inhibition. Loss of KEAP1, a negative regulator of NFE2L2/NRF2, modulated the response to BRAF, MEK, EGFR, and ALK inhibition in BRAF-, NRAS-, KRAS-, EGFR-, and ALK-mutant lung cancer cells. Treatment with inhibitors targeting the RTK/MAPK pathway increased reactive oxygen species (ROS) in cells with intact KEAP1, and loss of KEAP1 abrogated this increase. In addition, loss of KEAP1 altered cell metabolism to allow cells to proliferate in the absence of MAPK signaling. These observations suggest that alterations in the KEAP1/NRF2 pathway may promote survival in the presence of multiple inhibitors targeting the RTK/Ras/MAPK pathway.

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