Clinical Translation of Combined MAPK and Autophagy Inhibition in RAS Mutant Cancer

RAS (rat sarcoma virus) mutant cancers remain difficult to treat despite the advances in targeted therapy and immunotherapy. Targeted therapies against the components of mitogen-activated protein kinase (MAPK) pathways, including RAS, RAF, MEK, and ERK, have demonstrated activity in BRAF mutant and, in limited cases, RAS mutant cancer. RAS mutant cancers have been found to activate adaptive resistance mechanisms such as autophagy during MAPK inhibition. Here, we review the recent clinically relevant advances in the development of the MAPK pathway and autophagy inhibitors and focus on their application to RAS mutant cancers. We provide analysis of the preclinical rationale for combining the MAPK pathway and autophagy and highlight the most recent clinical trials that have been launched to capitalize on this potentially synthetic lethal approach to cancer therapy.

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LZTR1 is a regulator of RAS ubiquitination and signaling

Science ◽

10.1126/science.aap8210 ◽

2018 ◽

Vol 362 (6419) ◽

pp. 1171-1177 ◽

Cited By ~ 51

Author(s):

Johannes W. Bigenzahn ◽

Giovanna M. Collu ◽

Felix Kartnig ◽

Melanie Pieraks ◽

Gregory I. Vladimer ◽

...

Keyword(s):

Leucine Zipper ◽

Kinase Inhibitors ◽

Mapk Pathway ◽

Resistance Mechanisms ◽

Mitogen Activated Protein Kinase ◽

Loss Of Function ◽

Pathway Activation ◽

Mitogen Activated Protein ◽

Human Disorders ◽

Ras Isoforms

In genetic screens aimed at understanding drug resistance mechanisms in chronic myeloid leukemia cells, inactivation of the cullin 3 adapter protein-encoding leucine zipper-like transcription regulator 1 (LZTR1) gene led to enhanced mitogen-activated protein kinase (MAPK) pathway activity and reduced sensitivity to tyrosine kinase inhibitors. Knockdown of theDrosophila LZTR1orthologCG3711resulted in a Ras-dependent gain-of-function phenotype. Endogenous human LZTR1 associates with the main RAS isoforms. Inactivation ofLZTR1led to decreased ubiquitination and enhanced plasma membrane localization of endogenous KRAS (V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog). We propose that LZTR1 acts as a conserved regulator of RAS ubiquitination and MAPK pathway activation. BecauseLZTR1disease mutations failed to revert loss-of-function phenotypes, our findings provide a molecular rationale forLZTR1involvement in a variety of inherited and acquired human disorders.

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The Genomic Landscape of Thyroid Cancer Tumourigenesis and Implications for Immunotherapy

Cells ◽

10.3390/cells10051082 ◽

2021 ◽

Vol 10 (5) ◽

pp. 1082

Author(s):

Amandeep Singh ◽

Jeehoon Ham ◽

Joseph William Po ◽

Navin Niles ◽

Tara Roberts ◽

...

Keyword(s):

Thyroid Cancer ◽

Mapk Pathway ◽

Treatment Options ◽

Metastatic Potential ◽

Pi3k Pathway ◽

Mitogen Activated Protein Kinase ◽

Sequencing Data ◽

Genetic Aberrations ◽

Progression Model ◽

Mitogen Activated Protein

Thyroid cancer is the most prevalent endocrine malignancy that comprises mostly indolent differentiated cancers (DTCs) and less frequently aggressive poorly differentiated (PDTC) or anaplastic cancers (ATCs) with high mortality. Utilisation of next-generation sequencing (NGS) and advanced sequencing data analysis can aid in understanding the multi-step progression model in the development of thyroid cancers and their metastatic potential at a molecular level, promoting a targeted approach to further research and development of targeted treatment options including immunotherapy, especially for the aggressive variants. Tumour initiation and progression in thyroid cancer occurs through constitutional activation of the mitogen-activated protein kinase (MAPK) pathway through mutations in BRAF, RAS, mutations in the phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) pathway and/or receptor tyrosine kinase fusions/translocations, and other genetic aberrations acquired in a stepwise manner. This review provides a summary of the recent genetic aberrations implicated in the development and progression of thyroid cancer and implications for immunotherapy.

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Review of treatment and therapeutic targets in brain arteriovenous malformation

Journal of Cerebral Blood Flow & Metabolism ◽

10.1177/0271678x211026771 ◽

2021 ◽

pp. 0271678X2110267

Author(s):

Peipei Pan ◽

Shantel Weinsheimer ◽

Daniel Cooke ◽

Ethan Winkler ◽

Adib Abla ◽

...

Keyword(s):

Animal Models ◽

De Novo ◽

Mapk Pathway ◽

Treatment Options ◽

Therapeutic Targets ◽

Current Treatment ◽

Mitogen Activated Protein Kinase ◽

De Novo Mutations ◽

Genetic Syndromes ◽

Mitogen Activated Protein

Brain arteriovenous malformations (bAVM) are an important cause of intracranial hemorrhage (ICH), especially in younger patients. The pathogenesis of bAVM are largely unknown. Current understanding of bAVM etiology is based on studying genetic syndromes, animal models, and surgically resected specimens from patients. The identification of activating somatic mutations in the Kirsten rat sarcoma viral oncogene homologue (KRAS) gene and other mitogen-activated protein kinase ( MAPK) pathway genes has opened up new avenues for bAVM study, leading to a paradigm shift to search for somatic, de novo mutations in sporadic bAVMs instead of focusing on inherited genetic mutations. Through the development of new models and understanding of pathways involved in maintaining normal vascular structure and functions, promising therapeutic targets have been identified and safety and efficacy studies are underway in animal models and in patients. The goal of this paper is to provide a thorough review or current diagnostic and treatment tools, known genes and key pathways involved in bAVM pathogenesis to summarize current treatment options and potential therapeutic targets uncovered by recent discoveries.

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Expression of transgenes enriched in rare codons is enhanced by the MAPK pathway

Scientific Reports ◽

10.1038/s41598-020-78453-5 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Jackson Peterson ◽

Siqi Li ◽

Erin Kaltenbrun ◽

Ozgun Erdogan ◽

Christopher M. Counter

Keyword(s):

Amino Acids ◽

Protein Kinase ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Rare Codons ◽

Synonymous Codons ◽

Multiple Components ◽

Human Genes ◽

Regulatory Module ◽

Mitogen Activated Protein

AbstractThe ability to translate three nucleotide sequences, or codons, into amino acids to form proteins is conserved across all organisms. All but two amino acids have multiple codons, and the frequency that such synonymous codons occur in genomes ranges from rare to common. Transcripts enriched in rare codons are typically associated with poor translation, but in certain settings can be robustly expressed, suggestive of codon-dependent regulation. Given this, we screened a gain-of-function library for human genes that increase the expression of a GFPrare reporter encoded by rare codons. This screen identified multiple components of the mitogen activated protein kinase (MAPK) pathway enhancing GFPrare expression. This effect was reversed with inhibitors of this pathway and confirmed to be both codon-dependent and occur with ectopic transcripts naturally coded with rare codons. Finally, this effect was associated, at least in part, with enhanced translation. We thus identify a potential regulatory module that takes advantage of the redundancy in the genetic code to modulate protein expression.

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MKK3-p38 signaling promotes apoptosis and the early inflammatory response in the obstructed mouse kidney

AJP Renal Physiology ◽

10.1152/ajprenal.00010.2007 ◽

2007 ◽

Vol 293 (5) ◽

pp. F1556-F1563 ◽

Cited By ~ 44

Author(s):

Frank Y. Ma ◽

Greg H. Tesch ◽

Richard A. Flavell ◽

Roger J. Davis ◽

David J. Nikolic-Paterson

Keyword(s):

Inflammatory Response ◽

P38 Mapk ◽

Renal Injury ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Mrna Levels ◽

Direct Role ◽

Mitogen Activated Protein ◽

Early Inflammatory Response ◽

Induced Apoptosis

Activation of the p38 mitogen-activated protein kinase (MAPK) pathway induces inflammation, apoptosis, and fibrosis. However, little is known of the contribution of the upstream kinases, MMK3 and MKK6, to activation of the p38 kinase in the kidney and consequent renal injury. This study investigated the contribution of MKK3 to p38 MAPK activation and renal injury in the obstructed kidney. Groups of eight wild-type (WT) or Mkk3−/− mice underwent unilateral ureteric obstruction (UUO) and were killed 3 or 7 days later. Western blotting showed a marked increase in phospho-p38 (p-p38) MAPK in UUO WT kidney. The same trend of increased p-p38 MAPK was seen in the UUO Mkk3−/− kidney, although the actual level of p-p38 MAPK was significantly reduced compared with WT, and this could not be entirely compensated for by the increase in MKK6 expression in the Mkk3−/− kidney. Apoptosis of tubular and interstitial cells in WT UUO mice was reduced by 50% in Mkk3−/− UUO mice. Furthermore, cultured Mkk3−/− tubular epithelial cells showed resistance to H2O2-induced apoptosis, suggesting a direct role for MKK3-p38 signaling in tubular apoptosis. Upregulation of MCP-1 mRNA levels and macrophage infiltration seen on day 3 in WT UUO mice was significantly reduced in Mkk3−/− mice, but this difference was not evident by day 7. The development of renal fibrosis in Mkk3−/− UUO mice was not different from that seen in WT UUO mice. In conclusion, these studies identify discrete roles for MKK3-p38 signaling in renal cell apoptosis and the early inflammatory response in the obstructed kidney.

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Somatostatin stimulates intestinal NHE8 expression via p38 MAPK pathway

AJP Cell Physiology ◽

10.1152/ajpcell.00421.2010 ◽

2011 ◽

Vol 300 (2) ◽

pp. C375-C382 ◽

Cited By ~ 15

Author(s):

Chunhui Wang ◽

Hua Xu ◽

Huacong Chen ◽

Jing Li ◽

Bo Zhang ◽

...

Keyword(s):

P38 Mapk ◽

Mapk Pathway ◽

Somatostatin Receptor ◽

Peptide Hormone ◽

Mitogen Activated Protein Kinase ◽

Mapk Phosphorylation ◽

P38 Mapk Pathway ◽

Mitogen Activated Protein ◽

D Cells ◽

Human Intestinal Cells

Diarrhea is a common manifestation of gastrointestinal disorders. Diarrhea-induced losses of fluid and electrolyte could lead to dehydration and electrolyte imbalances, resulting in significant morbidity and mortality, especially in children living in developing countries. Somatostatin, a peptide hormone secreted by D-cells, plays an important role in regulating motility and intestinal Na+ absorption. Although octreotide, a somatostatin analog, is used to treat diarrhea, its mechanisms of action are unclear. Here we showed that octreotide increased brush-border membrane Na+/H+ exchanger 8 (NHE8) expression in the small intestine to the exclusion of other NHEs that participate in Na+ absorption. The same effect also occurred in human intestinal cells (Caco-2). We found that the increase of NHE8 expression by somatostatin required p38 mitogen-activated protein kinase (MAPK) activation. Furthermore, the somatostatin receptor SSTR2 antagonist CYN154806 could abolish somatostatin-induced NHE8 expression and p38 MAPK phosphorylation. Thus our data provided the first concrete evidence indicating that somatostatin stimulates intestinal Na+ absorption by increasing intestinal NHE8 expression through the SSTR2-p38 MAPK pathway.

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Ghrelin exerts a proliferative effect on a rat pituitary somatotroph cell line via the mitogen-activated protein kinase pathway

Acta Endocrinologica ◽

10.1530/eje.0.1510233 ◽

2004 ◽

pp. 233-240 ◽

Cited By ~ 99

Author(s):

AM Nanzer ◽

S Khalaf ◽

AM Mozid ◽

RC Fowkes ◽

MV Patel ◽

...

Keyword(s):

Cell Proliferation ◽

Protein Kinase ◽

Cell Line ◽

Kinase Inhibitor ◽

Thymidine Incorporation ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Gh3 Cells ◽

Rat Pituitary ◽

Mitogen Activated Protein

OBJECTIVES: Ghrelin is a brain-gut peptide with GH-releasing and appetite-inducing activities and a widespread tissue distribution. Ghrelin is the endogenous ligand of the GH secretagogue receptor type 1a (GHS-R1a), and both ghrelin and the GHS-R1a are expressed in the pituitary. There are conflicting data regarding the effects of ghrelin on cell proliferation. A positive effect on proliferation and activation of the mitogen-activated protein kinase (MAPK) pathway has been found in hepatoma, adipose, cardiomyocyte and prostate cell lines. However, ghrelin has also been shown to have anti-proliferative effects on breast, lung and thyroid cell lines. We therefore examined the effect of ghrelin on the rat pituitary cell line GH3. METHODS: RT-PCR was used for the detection of GHS-R1a and pre-proghrelin mRNA expression in GH3 cells. The effect of ghrelin on cell proliferation was studied using [(3)H]thymidine incorporation; cell counting and the activation of the MAPK pathway were studied using immunoblotting and inhibitors of the extracellular signal-regulated kinase 1 and 2 (ERK 1/2), protein kinase C (PKC) and tyrosine phosphatase pathways. RESULTS: GHS-R1a and ghrelin mRNA expression were detected in GH3 cells. Ghrelin, at 10(-10) to 10(-6) M concentrations, significantly increased [(3)H]thymidine incorporation (at 10(-9) M, 183+/-13% (means+/-s.e.m.) compared with untreated controls), while 12-phorbol 13-myristate acetate (PMA) at 10(-7) M (used as a positive control) caused a 212+/-14% increase. A reproducible stimulatory effect of desoctanoyl ghrelin was also observed on [(3)H]thymidine incorporation (135+/-5%; P<0.01 at 10(-9) M compared with control), as well as on the cell count (control 6.8 x 10(4)+/-8.7 x 10(3) cells/ml vs desoctanoyl ghrelin (10(-9) M) 1.04 x 10(5)+/-7.5 x 10(3) cells/ml; P<0.01). Ghrelin caused a significant increase in phosphorylated ERK 1/2 in immunoblotting, while desoctanoyl ghrelin showed a smaller but also significant stimulatory effect. The positive effect of ghrelin and desoctanoyl ghrelin on [(3)H]thymidine incorporation was abolished by the MAPK kinase inhibitor U0126, the PKC inhibitor GF109203X and the tyrosine kinase inhibitor tyrphostin 23, suggesting that the ghrelin-induced cell proliferation of GH3 cells is mediated both via a PKC-MAPK-dependent pathway and via a tyrosine kinase-dependent pathway. This could also be clearly demonstrated by Western blot analysis, where a transient increase in ERK 1/2 phosphorylation by ghrelin was attenuated by all three inhibitors. CONCLUSION: We have shown a novel role for ghrelin in stimulating the proliferation of a somatotroph pituitary tumour cell line, suggesting that ERK activation is involved in mediating the effects of ghrelin on cell proliferation. Desoctanoyl ghrelin showed a similar effect. As ghrelin has been shown to be expressed in both normal and adenomatous pituitary tissue, locally produced ghrelin may play a role in pituitary tumorigenesis via an autocrine/paracrine pathway.

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Camel Milk Attenuates Rheumatoid Arthritis Via Inhibition of Mitogen Activated Protein Kinase Pathway

Cellular Physiology and Biochemistry ◽

10.1159/000480527 ◽

2017 ◽

Vol 43 (2) ◽

pp. 540-552 ◽

Cited By ~ 17

Author(s):

Hany H. Arab ◽

Samir A. Salama ◽

Tamer M. Abdelghany ◽

Hany A. Omar ◽

El-Shaimaa A. Arafa ◽

...

Keyword(s):

Rheumatoid Arthritis ◽

Mapk Pathway ◽

Lipid Peroxide ◽

Mitogen Activated Protein Kinase ◽

Camel Milk ◽

Tnf Α ◽

Mitogen Activated Protein ◽

Anti Oxidant ◽

Cox 2 ◽

Anti Inflammatory

Background/Aims: Camel milk (CM) has shown beneficial anti-inflammatory actions in several experimental and clinical settings. So far, its effect on rheumatoid arthritis (RA) has not been previously explored. Thus, the current work aimed to evaluate the effects of CM in Adjuvant-induced arthritis and air pouch edema models in rats, which mimic human RA. Methods: CM was administered at 10 ml/kg orally for 3 weeks starting on the day of Freund’s adjuvant paw inoculation. The levels of TNF-α and IL-10 were measured by ELISA while the protein expression of NF-κBp65, COX-2 and iNOS was detected by immunohistochemistry. The expression of MAPK target proteins was assessed by Western blotting. Results: CM attenuated paw edema, arthritic index and gait score along with dorsal pouch inflammatory cell migration. CM lowered the TNF-α and augmented the anti-inflammatory IL-10 levels in sera and exudates of arthritic rats. It also attenuated the expression of activated NF-κBp65, COX-2 and iNOS in the lining of the dorsal pouch. Notably, CM inhibited the MAPK pathway signal transduction via lowering the phosphorylation of p38 MAPK, ERK1/2 and JNK1/2 in rat hind paws. Additionally, CM administration lowered the lipid peroxide and nitric oxide levels and boosted glutathione and total anti-oxidant capacity in sera and exudates of animals. Conclusion: The observed CM downregulation of the arthritic process may support the interest of CM consumption as an adjunct approach for the management of RA.

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The p38/MK2 Axis in Monocytes of Fibromyalgia Syndrome Patients: An Explorative Study

Medicina ◽

10.3390/medicina57040396 ◽

2021 ◽

Vol 57 (4) ◽

pp. 396

Author(s):

Boya Nugraha ◽

Renate Scheibe ◽

Christoph Korallus ◽

Matthias Gaestel ◽

Christoph Gutenbrunner

Keyword(s):

Pain Management ◽

P38 Mapk ◽

Fibromyalgia Syndrome ◽

Mapk Pathway ◽

Mitogen Activated Protein Kinase ◽

Pain Syndromes ◽

Novel Approach ◽

Mitogen Activated Protein ◽

The Mean ◽

Direct Target

Background and Objectives: The aetiology and pathomechanism of fibromyalgia syndrome 12 (FMS) as one of chronic pain syndromes still need to be further elucidated. Mitogen-activated protein kinase (MAPK) pathway has been proposed as a novel approach in pain management. Since the major symptom of fibromyalgia syndrome (FMS) patients is pain, it became of interest whether MAPK pathways, such as the stress-activated p38 MAPK/MK2 axis, are activated in FMS patients. Therefore, this study aimed at determining p38 MAPK/MK2 in FMS patients. Materials and Methods: Phosphorylation of MAPK-activated protein kinases 2 (MK2), a direct target of p38 MAPK, was measured in monocytes of FMS and healthy controls (HCs) to monitor the activity of this pathway. Results: The mean level of phosphorylated MK2 was fivefold higher in FMS patients as compared to HCs (p < 0.001). Subgroup analysis revealed that antidepressants did not influence the activity of MK2 in FMS patients. Conclusions: This result indicates that the p38/MK2 pathway could be involved in the pathomechanism of FMS, could act as a clinical marker for FMS, and could be a possible target for pain management in FMS patients.

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Molecular Bases of Cutaneous and Uveal Melanomas

Pathology Research International ◽

10.4061/2011/159421 ◽

2011 ◽

Vol 2011 ◽

pp. 1-8 ◽

Cited By ~ 5

Author(s):

Sudeep Gaudi ◽

Jane L. Messina

Keyword(s):

Mapk Pathway ◽

Susceptibility Gene ◽

Low Frequency ◽

Preliminary Evidence ◽

Mitogen Activated Protein Kinase ◽

Molecular Pathways ◽

Skin Cancers ◽

Mitogen Activated Protein ◽

Sporadic Cases ◽

Molecular Bases

Intensive research in recent years has begun to unlock the mysteries surrounding the molecular pathogenesis of melanoma, the deadliest of skin cancers. The high-penetrance, low-frequency susceptibility gene CDKN2A produces tumor suppressor proteins that function in concert with p53 and retinoblastoma protein to thwart melanomagenesis. Aberrant CDKN2A gene products have been implicated in a great many cases of familial cutaneous melanoma. Sporadic cases, on the other hand, often involve constitutive signal transduction along the mitogen-activated protein kinase (MAPK) pathway, with particular focus falling upon mutated RAS and RAF protooncogenes. The proliferative effects of the MAPK pathway may be complemented by the antiapoptotic signals of the PI3K/AKT pathway. After skin, melanoma most commonly affects the eye. Data for the constitutive activation of the MAPK pathway in uveal melanoma exists as well, however, not through mutations of RAS and RAF. Rather, evidence implicates the proto-oncogene GNAQ. In the following discussion, we review the major molecular pathways implicated in both familial and sporadic cutaneous melanomagenesis, the former accounting for approximately 10% of cases. Additionally, we discuss the molecular pathways for which preliminary evidence suggests a role in uveal melanomagenesis.

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