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Melanoma Research Oct 2023For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard...
For patients with locally advanced or metastatic melanoma who have BRAF V600 activating mutations, combination therapy with BRAF and MEK inhibitors is now the standard of care. The combination of encorafenib, a highly selective adenosine triphosphate-competitive BRAF inhibitor, plus binimetinib, a potent, selective, allosteric, non-adenosine triphosphate-competitive MEK1/2 inhibitor, was approved by the US Food and Drug Administration for unresectable or metastatic melanoma with BRAF V600E or V600K mutations based on data from the phase III COLUMBUS study (NCT01909453). Clinical data evaluating BRAF and MEK inhibitor combinations in advanced melanoma indicate a specific profile of adverse events that includes serious retinopathy, skin disorders, and cardiovascular toxicities. Here we provide an overview of the rationale for combining BRAF and MEK inhibitors for the treatment of melanoma, long-term safety results from COLUMBUS, and guidance on managing the most common adverse events associated with this combination based on clinical experience. Proactive and appropriate management of adverse events can allow for longer treatment durations and may result in better treatment outcomes.
Topics: Humans; Melanoma; Skin Neoplasms; Proto-Oncogene Proteins B-raf; Antineoplastic Combined Chemotherapy Protocols; Protein Kinase Inhibitors; Mutation; Mitogen-Activated Protein Kinase Kinases
PubMed: 37534686
DOI: 10.1097/CMR.0000000000000891 -
Pathology Oncology Research : POR 2023KRAS mutant lung cancer is the most prevalent molecular subclass of adenocarcinoma (LUAD), which is a heterogenous group depending on the mutation-type which affects not... (Review)
Review
KRAS mutant lung cancer is the most prevalent molecular subclass of adenocarcinoma (LUAD), which is a heterogenous group depending on the mutation-type which affects not only the function of the oncogene but affects the biological behavior of the cancer as well. Furthermore, KRAS mutation affects radiation sensitivity but leads also to bevacizumab and bisphosphonate resistance as well. It was highly significant that allele specific irreversible inhibitors have been developed for the smoking associated G12C mutant KRAS (sotorasib and adagrasib). Based on trial data both sotorasib and adagrasib obtained conditional approval by FDA for the treatment of previously treated advanced LUAD. Similar to other target therapies, clinical administration of KRASG12C inhibitors (sotorasib and adagrasib) resulted in acquired resistance due to various genetic changes not only in KRAS but in other oncogenes as well. Recent clinical studies are aiming to increase the efficacy of G12C inhibitors by novel combination strategies.
Topics: Humans; Proto-Oncogene Proteins p21(ras); Adenocarcinoma of Lung; Lung Neoplasms; Mutation; Biology; Acetonitriles; Piperazines; Pyrimidines
PubMed: 38239281
DOI: 10.3389/pore.2023.1611580 -
Postepy Biochemii Sep 2023Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the...
Malignant melanoma is a dangerous skin cancer, accounting for the majority of skin cancer-related deaths. Many patients with this cancer have the V600E mutation in the BRAF gene. This mutation causes constitutive activation of the MAPK/ERK signaling pathway, significantly contributing to the process of carcinogenesis. We discuss the drug design process on the example of a specific BRAF V600E inhibitor, vemurafenib. We begin with the most commonly used drug design methods. The second part of the article focuses on vemurafenib. We analyze the invention of this BRAF V600E inhibitor and its analogue as well as the course of three stages of clinical trials. Then we provide information about other popular drugs for malignant melanoma, i.e. dacarbazine, ipilimumab and dabrafenib, and about the advantages of therapy with the simultaneous use of two inhibitors. Finally, we briefly discuss the role of artificial intelligence in the future of drug design.
Topics: Humans; Vemurafenib; Antineoplastic Agents; Proto-Oncogene Proteins B-raf; Artificial Intelligence; Indoles; Sulfonamides; Melanoma; Skin Neoplasms; Protein Kinase Inhibitors; Mutation; Drug Resistance, Neoplasm; Melanoma, Cutaneous Malignant
PubMed: 38019740
DOI: 10.18388/pb.2021_498 -
Life Sciences Jul 2024Erdheim Chester Disease (ECD) is a rare histiocytic disorder marked by infiltration of organs with CD68 histiocytes. ECD stems from mutations of BRAF and MAP2K1 in... (Review)
Review
Erdheim Chester Disease (ECD) is a rare histiocytic disorder marked by infiltration of organs with CD68 histiocytes. ECD stems from mutations of BRAF and MAP2K1 in hematopoietic stem and progenitor cells (HSPCs), which further differentiate into monocytes and histiocytes. Histopathology reveals lipid-containing histiocytes, which test positive for CD68 and CD133 in immunohistochemistry. Signs and symptoms vary and depend on the organ/s of manifestation. Definitive radiological results associated with ECD include hairy kidney, coated aorta, and cardiac pseudotumor. Treatment options primarily include anti-cytokine therapy and inhibitors of BRAF and MEK signaling.
Topics: Erdheim-Chester Disease; Humans; Proto-Oncogene Proteins B-raf; Histiocytes
PubMed: 38710283
DOI: 10.1016/j.lfs.2024.122692 -
The Journal of Experimental Medicine Aug 2023Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for...
Type I interferons are important antiviral cytokines, but prolonged interferon production is detrimental to the host. The TLR3-driven immune response is crucial for mammalian antiviral immunity, and its intracellular localization determines induction of type I interferons; however, the mechanism terminating TLR3 signaling remains obscure. Here, we show that the E3 ubiquitin ligase ZNRF1 controls TLR3 sorting into multivesicular bodies/lysosomes to terminate signaling and type I interferon production. Mechanistically, c-Src kinase activated by TLR3 engagement phosphorylates ZNRF1 at tyrosine 103, which mediates K63-linked ubiquitination of TLR3 at lysine 813 and promotes TLR3 lysosomal trafficking and degradation. ZNRF1-deficient mice and cells are resistant to infection by encephalomyocarditis virus and SARS-CoV-2 because of enhanced type I interferon production. However, Znrf1-/- mice have exacerbated lung barrier damage triggered by antiviral immunity, leading to enhanced susceptibility to respiratory bacterial superinfections. Our study highlights the c-Src-ZNRF1 axis as a negative feedback mechanism controlling TLR3 trafficking and the termination of TLR3 signaling.
Topics: Animals; Mice; Antiviral Agents; COVID-19; Interferon Type I; SARS-CoV-2; Toll-Like Receptor 3; Genes, src
PubMed: 37158982
DOI: 10.1084/jem.20220727 -
The Journal of Clinical Investigation Nov 2023The PI3K/AKT/mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit, likely owing to their lack of effects on 4EBP1. We hypothesized...
The PI3K/AKT/mTOR pathway is commonly dysregulated in cancer. Rapalogs exhibit modest clinical benefit, likely owing to their lack of effects on 4EBP1. We hypothesized that bi-steric mTORC1-selective inhibitors would have greater potential for clinical benefit than rapalogs in tumors with mTORC1 dysfunction. We assessed this hypothesis in tumor models with high mTORC1 activity both in vitro and in vivo. Bi-steric inhibitors had strong growth inhibition, eliminated phosphorylated 4EBP1, and induced more apoptosis than rapamycin or MLN0128. Multiomics analysis showed extensive effects of the bi-steric inhibitors in comparison with rapamycin. De novo purine synthesis was selectively inhibited by bi-sterics through reduction in JUN and its downstream target PRPS1 and appeared to be the cause of apoptosis. Hence, bi-steric mTORC1-selective inhibitors are a therapeutic strategy to treat tumors driven by mTORC1 hyperactivation.
Topics: Mechanistic Target of Rapamycin Complex 1; MTOR Inhibitors; Phosphatidylinositol 3-Kinases; Cell Line, Tumor; Sirolimus; Apoptosis; Cell Proliferation; Proto-Oncogene Proteins c-akt
PubMed: 37909334
DOI: 10.1172/JCI167861 -
Oncotarget Dec 2023
Topics: Humans; Cytostatic Agents; Signal Transduction; Proto-Oncogene Proteins c-akt; PTEN Phosphohydrolase; Cell Proliferation; Cell Line, Tumor; Neoplasms
PubMed: 38039406
DOI: 10.18632/oncotarget.28488 -
Nature Communications May 2024Post-translational modifications of proteins in malignant transformation and tumor maintenance of pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS...
Post-translational modifications of proteins in malignant transformation and tumor maintenance of pancreatic ductal adenocarcinoma (PDAC) in the context of KRAS signaling remain poorly understood. Here, we use the KPC mouse model to examine the effect of palmitoylation on pancreatic cancer progression. ZDHHC20, upregulated by KRAS, is abnormally overexpressed and associated with poor prognosis in patients with pancreatic cancer. Dysregulation of ZDHHC20 promotes pancreatic cancer progression in a palmitoylation-dependent manner. ZDHHC20 inhibits the chaperone-mediated autophagic degradation of YTHDF3 through S-palmitoylation of Cys474, which can result in abnormal accumulation of the oncogenic product MYC and thereby promote the malignant phenotypes of cancer cells. Further, we design a biologically active YTHDF3-derived peptide to competitively inhibit YTHDF3 palmitoylation mediated by ZDHHC20, which in turn downregulates MYC expression and inhibits the progression of KRAS mutant pancreatic cancer. Thus, these findings highlight the therapeutic potential of targeting the ZDHHC20-YTHDF3-MYC signaling axis in pancreatic cancer.
Topics: Animals; Humans; Pancreatic Neoplasms; Proto-Oncogene Proteins c-myc; Acyltransferases; Lipoylation; Mice; Cell Line, Tumor; Proto-Oncogene Proteins p21(ras); Carcinoma, Pancreatic Ductal; Disease Progression; Gene Expression Regulation, Neoplastic; RNA, Messenger; RNA-Binding Proteins; Male; Signal Transduction; RNA Stability; Female
PubMed: 38821916
DOI: 10.1038/s41467-024-49105-3 -
Biomedicine & Pharmacotherapy =... Oct 2023Premature ovarian insufficiency (POI) is clinically irreversible and seriously damages female fertility. We previously demonstrated that menstrual blood stromal cells...
Exosomes derived from menstrual blood stromal cells ameliorated premature ovarian insufficiency and granulosa cell apoptosis by regulating SMAD3/AKT/MDM2/P53 pathway via delivery of thrombospondin-1.
Premature ovarian insufficiency (POI) is clinically irreversible and seriously damages female fertility. We previously demonstrated that menstrual blood stromal cells (MenSCs)-derived exosomes (EXOs) effectively improved ovarian functions in the POI rat model. In this study, we investigated whether TSP1 is the key component in EXOs to ameliorate ovarian functions and further explored the molecular mechanism of EXOs in improving granulosa cell (GCs) activities. Our results demonstrated that knockdown TSP1 significantly debilitated the therapeutic effect of EXOs on estrous cyclicity, ovarian morphology, follicle numbers and pregnancy outcomes in 4-vinylcyclohexene diepoxide (VCD) induced POI rat model. In addition, EXOs treatment significantly promoted the activities and inhibited the apoptosis of VCD induced granulosa cells in vitro. Moreover, EXOs stimulation markedly activated the phosphorylation of SMAD3(Ser425) and AKT(Ser473), up-regulated the expressions of BCL2 and MDM2 as well as down-regulated the expressions of CASPASE3, CASPASE8, P53 and BAX. All these effects were supressed by SIS3, a inhibitor of TGF1/SMAD3. Our study revealed the key role of TSP1 in EXOs in improving POI pathology, restoring ovarian functions and GCs activities, andprovided a promising basis for EXOs in the treatment of ovarian dysfunction.
Topics: Animals; Female; Humans; Pregnancy; Rats; Apoptosis; Exosomes; Granulosa Cells; Menstruation; Primary Ovarian Insufficiency; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins c-mdm2; Smad3 Protein; Stromal Cells; Thrombospondins; Tumor Suppressor Protein p53
PubMed: 37573658
DOI: 10.1016/j.biopha.2023.115319 -
The Journal of Biological Chemistry Apr 2024FOXO1 is a transcription factor and potential tumor suppressor that is negatively regulated downstream of PI3K-PKB/AKT signaling. Paradoxically, FOXO also promotes tumor...
FOXO1 is a transcription factor and potential tumor suppressor that is negatively regulated downstream of PI3K-PKB/AKT signaling. Paradoxically, FOXO also promotes tumor growth, but the detailed mechanisms behind this role of FOXO are not fully understood. In this study, we revealed a molecular cascade by which the Thr24 residue of FOXO1 is phosphorylated by AKT and is dephosphorylated by calcineurin, which is a Ca-dependent protein phosphatase. Curiously, single nucleotide somatic mutations of FOXO1 in cancer occur frequently at and near Thr24. Using a calcineurin inhibitor and shRNA directed against calcineurin, we revealed that calcineurin-mediated dephosphorylation of Thr24 regulates FOXO1 protein stability. We also found that FOXO1 binds to the promoter region of MDM2 and activates transcription, which in turn promotes MDM2-mediated ubiquitination and degradation of p53. FOXO3a and FOXO4 are shown to control p53 activity; however, the significance of FOXO1 in p53 regulation remains largely unknown. Supporting this notion, FOXO1 depletion increased p53 and p21 protein levels in association with the inhibition of cell proliferation. Taken together, these results indicate that FOXO1 is stabilized by calcineurin-mediated dephosphorylation and that FOXO1 supports cancer cell proliferation by promoting MDM2 transcription and subsequent p53 degradation.
Topics: Proto-Oncogene Proteins c-mdm2; Humans; Tumor Suppressor Protein p53; Forkhead Box Protein O1; Calcineurin; Proteolysis; Phosphorylation; Cell Proliferation; Ubiquitination; Cell Line, Tumor; Neoplasms; Forkhead Transcription Factors; Proto-Oncogene Proteins c-akt; Protein Stability
PubMed: 38519029
DOI: 10.1016/j.jbc.2024.107209