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Cancer Cell Jun 2024KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity,...
KRAS G12D is the most frequently mutated oncogenic KRAS subtype in solid tumors and remains undruggable in clinical settings. Here, we developed a high affinity, selective, long-acting, and non-covalent KRAS G12D inhibitor, HRS-4642, with an affinity constant of 0.083 nM. HRS-4642 demonstrated robust efficacy against KRAS G12D-mutant cancers both in vitro and in vivo. Importantly, in a phase 1 clinical trial, HRS-4642 exhibited promising anti-tumor activity in the escalating dosing cohorts. Furthermore, the sensitization and resistance spectrum for HRS-4642 was deciphered through genome-wide CRISPR-Cas9 screening, which unveiled proteasome as a sensitization target. We further observed that the proteasome inhibitor, carfilzomib, improved the anti-tumor efficacy of HRS-4642. Additionally, HRS-4642, either as a single agent or in combination with carfilzomib, reshaped the tumor microenvironment toward an immune-permissive one. In summary, this study provides potential therapies for patients with KRAS G12D-mutant cancers, for whom effective treatments are currently lacking.
PubMed: 38942026
DOI: 10.1016/j.ccell.2024.06.001 -
Biomedicine & Pharmacotherapy =... Jun 2024Melanoma cells express high levels of CD73 that produce extracellular immunosuppressive adenosine. Changes in the CD73 expression occur in response to tumor...
Melanoma cells express high levels of CD73 that produce extracellular immunosuppressive adenosine. Changes in the CD73 expression occur in response to tumor environmental factors, contributing to tumor phenotype plasticity and therapeutic resistance. Previously, we have observed that CD73 expression can be up-regulated on the surface of melanoma cells in response to nutritional stress. Here, we explore the mechanism by which melanoma cells release soluble CD73 under low nutrient availability and whether this might be affected by agents targeting the proto-oncogene B-Raf (BRAF). We found that starved melanoma cells can release high levels of CD73, able to convert AMP into adenosine, and this activity is abrogated by selective CD73 inhibitors, APCP or PSB-12489. The release of CD73 from melanoma cells is mediated by the matrix metalloproteinase MMP-9. Indeed, MMP-9 inhibitors significantly reduce the levels of CD73 released from the cells, while its surface levels increase. Of relevance, melanoma cells, harboring an activating BRAF mutation, upon treatment with dabrafenib or vemurafenib, show a strong reduction of CD73 cell expression and reduced levels of CD73 released into the extracellular space. Conversely, melanoma cells resistant to dabrafenib show high expression of membrane-bound CD73 and soluble CD73 released into the culture medium. In summary, our data indicate that CD73 is released from melanoma cells. The expression of CD73 is associated with response to BRAF inhibitors. Melanoma cells developing resistance to dabrafenib show increased expression of CD73, including soluble CD73 released from cells, suggesting that CD73 is involved in acquiring resistance to treatment.
PubMed: 38941889
DOI: 10.1016/j.biopha.2024.117033 -
International Immunopharmacology Jun 2024Psoriasis, a chronic autoimmune skin disorder, causes rapid and excessive skin cell growth due to immune system dysfunction. Numerous studies have shown that flavonoids... (Review)
Review
Flavonoid compounds and their synergistic effects: Promising approaches for the prevention and treatment of psoriasis with emphasis on keratinocytes - A systematic and mechanistic review.
Psoriasis, a chronic autoimmune skin disorder, causes rapid and excessive skin cell growth due to immune system dysfunction. Numerous studies have shown that flavonoids have anti-psoriatic effects by modulating various molecular mechanisms involved in inflammation, cytokine production, keratinocyte proliferation, and more. This study reviewed experimental data reported in scientific literature and used network analysis to identify the potential biological roles of flavonoids' targets in treating psoriasis. 947 records from Web of Sciences, ScienceDirect database, Scopus, PubMed, and Cochrane library were reviewed without limitations until June 26, 2023. 66 articles were included in the systematic review. The ten genes with the highest scores, including interleukin (IL)-10, IL-12A, IL-1β, IL-6, Tumor necrosis factor-α (TNF-α), Janus kinase 2 (JAK 2), Jun N-terminal kinase (JUN), Proto-oncogene tyrosine-protein kinase Src (SRC), Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), and Signal transducer and activator of transcription 3 (STAT3), were identified as the hub genes. KEGG pathway analysis identified connections related to inflammation and autoimmune responses, which are key characteristics of psoriasis. IL-6, STAT3, and JUN's presence in both hub and enrichment genes suggests their important role in flavonoid's effect on psoriasis. This comprehensive study highlights how flavonoids can target biological processes in psoriasis, especially when combined for enhanced effectiveness.
PubMed: 38941673
DOI: 10.1016/j.intimp.2024.112561 -
Medicine Jun 2024Thyroglossal duct carcinoma, a rare clinical condition characterized by ectopic thyroid adenocarcinoma within thyroglossal duct cysts (TGDCs), typically confirmed... (Review)
Review
RATIONALE
Thyroglossal duct carcinoma, a rare clinical condition characterized by ectopic thyroid adenocarcinoma within thyroglossal duct cysts (TGDCs), typically confirmed through intraoperative rapid pathology, this condition generally has a favorable prognosis. Nevertheless, comprehensive treatment guidelines across all disease stages are lacking, the purpose of this study is to report 1 case of the disease and propose the treatment plan for each stage of the disease.
PATIENT CONCERNS
A patient presented with thyroid swelling, classified as C-TIRADS 4A following a physical examination. Preoperative thyroid puncture identified papillary thyroid carcinoma, and genetic testing revealed a BRAF gene exon 15-point mutation. Ancillary tests showed a slightly decreased thyroid stimulating hormone (TSH) level (0.172) with no other significant abnormalities.
DIAGNOSES
Preoperative fine-needle aspiration cytology (FNAC) confirmed right-side thyroid cancer. Intraoperative exploration uncovered a TGDC and intraoperative rapid pathology confirmed thyroglossal duct carcinoma.
INTERVENTIONS
A Sistrunk operation and ipsilateral thyroidectomy were performed.
OUTCOMES
Postoperative recovery was satisfactory.
LESSONS
Thyroglossal duct carcinoma is a rare disease affecting the neck. Due to limited clinical cases and the favorable prognosis associated with this condition, there is currently no established set of diagnostic and treatment guidelines. According to tumor size, lymph node metastasis, thyroid status and other factors, the corresponding treatment methods were established for each stage of thyroglossal duct cancer, which laid the foundation for the subsequent treatment development of this disease.
Topics: Humans; Thyroglossal Cyst; Thyroid Neoplasms; Thyroid Cancer, Papillary; Female; Thyroidectomy; Male; Proto-Oncogene Proteins B-raf; Adult; Biopsy, Fine-Needle
PubMed: 38941410
DOI: 10.1097/MD.0000000000038540 -
PloS One 2024Prenatal alcohol exposure (PAE) causes cognitive impairment and a distinctive craniofacial dysmorphology, due in part to apoptotic losses of the pluripotent cranial...
Prenatal alcohol exposure (PAE) causes cognitive impairment and a distinctive craniofacial dysmorphology, due in part to apoptotic losses of the pluripotent cranial neural crest cells (CNCs) that form facial bones and cartilage. We previously reported that PAE rapidly represses expression of >70 ribosomal proteins (padj = 10-E47). Ribosome dysbiogenesis causes nucleolar stress and activates p53-MDM2-mediated apoptosis. Using primary avian CNCs and the murine CNC line O9-1, we tested whether nucleolar stress and p53-MDM2 signaling mediates this apoptosis. We further tested whether haploinsufficiency in genes that govern ribosome biogenesis, using a blocking morpholino approach, synergizes with alcohol to worsen craniofacial outcomes in a zebrafish model. In both avian and murine CNCs, pharmacologically relevant alcohol exposure (20mM, 2hr) causes the dissolution of nucleolar structures and the loss of rRNA synthesis; this nucleolar stress persisted for 18-24hr. This was followed by reduced proliferation, stabilization of nuclear p53, and apoptosis that was prevented by overexpression of MDM2 or dominant-negative p53. In zebrafish embryos, low-dose alcohol or morpholinos directed against ribosomal proteins Rpl5a, Rpl11, and Rps3a, the Tcof homolog Nolc1, or mdm2 separately caused modest craniofacial malformations, whereas these blocking morpholinos synergized with low-dose alcohol to reduce and even eliminate facial elements. Similar results were obtained using a small molecule inhibitor of RNA Polymerase 1, CX5461, whereas p53-blocking morpholinos normalized craniofacial outcomes under high-dose alcohol. Transcriptome analysis affirmed that alcohol suppressed the expression of >150 genes essential for ribosome biogenesis. We conclude that alcohol causes the apoptosis of CNCs, at least in part, by suppressing ribosome biogenesis and invoking a nucleolar stress that initiates their p53-MDM2 mediated apoptosis. We further note that the facial deficits that typify PAE and some ribosomopathies share features including reduced philtrum, upper lip, and epicanthal distance, suggesting the facial deficits of PAE represent, in part, a ribosomopathy.
Topics: Animals; Neural Crest; Zebrafish; Ribosomes; Ethanol; Tumor Suppressor Protein p53; Apoptosis; Mice; Proto-Oncogene Proteins c-mdm2; Cell Nucleolus; Ribosomal Proteins; Skull; Zebrafish Proteins
PubMed: 38941348
DOI: 10.1371/journal.pone.0304557 -
Discover Oncology Jun 2024The long noncoding DANCR functions as a tumor oncogene in many cancers, including colorectal cancer (CRC). However, the molecular mechanism of DANCR in CRC has not been...
The long noncoding DANCR functions as a tumor oncogene in many cancers, including colorectal cancer (CRC). However, the molecular mechanism of DANCR in CRC has not been explored. This study probed the function and potential mechanism by which DANCR contributes to the progression of CRC. The obtained data indicated that DANCR is overexpressed in CRC tissues and cell lines. Knockdown of DANCR hindered CRC cell proliferation, which was mediated by cyclin D1 and CDK4. Bioinformatic analysis, luciferase reporter assays and subcellular fractionation verified that DANCR directly binds to miR-508-5p. Moreover, DANCR acts as a miR-508-5p ceRNA to regulate expression of ATF1. In addition, upregulation of DANCR is attributed to H3K27 acetylation at the promoter region. In conclusion, our study confirmed that activation of lncRNA DANCR by H3K27 acetylation has an oncogenic role in CRC progression and provides a potential therapeutic target for CRC.
PubMed: 38940959
DOI: 10.1007/s12672-024-01124-8 -
Acta Crystallographica. Section F,... Jul 2024Protein tyrosine phosphatase non-receptor type 21 (PTPN21) is a cytosolic protein tyrosine phosphatase that regulates cell growth and invasion. Due to its oncogenic...
Protein tyrosine phosphatase non-receptor type 21 (PTPN21) is a cytosolic protein tyrosine phosphatase that regulates cell growth and invasion. Due to its oncogenic properties, PTPN21 has recently emerged as a potential therapeutic target for cancer. In this study, the three-dimensional structure of the PTPN21 FERM domain was determined at 2.1 Å resolution by X-ray crystallography. The crystal structure showed that this domain harbors canonical FERM folding and consists of three subdomains that are tightly packed via highly conserved intramolecular hydrophobic interactions. Consistent with this, the PTPN21 FERM domain shares high structural homology with several other FERM domains. Moreover, structural superimposition demonstrated two putative protein-binding sites of the PTPN21 FERM domain, which are presumed to be associated with interaction with its binding partner, kinesin family member 1C. Thus, these data suggest that the FERM domain of PTPN21 serves as a module that mediates protein-protein interaction, like other FERM domains.
PubMed: 38940939
DOI: 10.1107/S2053230X24005260 -
Journal of Biochemical and Molecular... Jul 2024
Short communication on "new insights into the combined toxicity of aflatoxin B1 and Fumonisin B1 in HepG2 cells using Seahorse respirometry analysis and RNA transcriptome sequencing".
Topics: Humans; Aflatoxin B1; Fumonisins; Hep G2 Cells; Transcriptome; Sequence Analysis, RNA
PubMed: 38940674
DOI: 10.1002/jbt.23756 -
Cancer Biology & Medicine Jun 2024Targeted therapy is crucial for advanced colorectal cancer (CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs,... (Review)
Review
Targeted therapy is crucial for advanced colorectal cancer (CRC) positive for genetic drivers. With advances in deep sequencing technology and new targeted drugs, existing standard molecular pathological detection systems and therapeutic strategies can no longer meet the requirements for careful management of patients with advanced CRC. Thus, rare genetic variations require diagnosis and targeted therapy in clinical practice. Rare gene mutations, amplifications, and rearrangements are usually associated with poor prognosis and poor response to conventional therapy. This review summarizes the clinical diagnosis and treatment of rare genetic variations, in genes including erb-b2 receptor tyrosine kinase 2 (ERBB2), B-Raf proto-oncogene, serine/threonine kinase (BRAF), ALK receptor tyrosine kinase/ROS proto-oncogene 1, receptor tyrosine kinase (ALK/ROS1), neurotrophic receptor tyrosine kinases (NTRKs), ret proto-oncogene (RET), fibroblast growth factor receptor 2 (FGFR2), and epidermal growth factor receptor (EGFR), to enhance understanding and identify more accurate personalized treatments for patients with rare genetic variations.
Topics: Humans; Colorectal Neoplasms; Proto-Oncogene Mas; Genetic Variation; Mutation; Proto-Oncogene Proteins c-ret; Molecular Targeted Therapy; Proto-Oncogene Proteins B-raf; Precision Medicine; Biomarkers, Tumor; Protein-Tyrosine Kinases; Proto-Oncogene Proteins
PubMed: 38940668
DOI: 10.20892/j.issn.2095-3941.2024.0026 -
Cancer Medicine Jul 2024Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and...
INTRODUCTION
Nucleoporin 98 (NUP98) fusion proteins are recurrently found in leukemia and are associated with unfavorable clinical outcomes. They are distributed to the nucleus and contribute to leukemogenesis via aberrant transcriptional regulation. We previously identified NUP98-BPTF (NB) fusion in patients with T-cell acute lymphoblastic leukemia (T-ALL) using next-generation sequencing. The FG-repeat of NUP98 and the PHD finger and bromodomain of bromodomain PHD finger transcription factor (BPTF) are retained in the fusion. Like other NUP98 fusion proteins, NB is considered to regulate genes that are essential for leukemogenesis. However, its target genes or pathways remain unknown.
MATERIALS AND METHODS
To investigate the potential oncogenic properties of the NB fusion protein, we lentivirally transduced a doxycycline-inducible NB expression vector into mouse NIH3T3 fibroblasts and human Jurkat T-ALL cells.
RESULTS
NB promoted the transformation of mouse NIH3T3 fibroblasts by upregulating the proto-oncogene Pim1, which encodes a serine/threonine kinase. NB transcriptionally regulated Pim1 expression by binding to its promoter and activated MYC and mTORC1 signaling. PIM1 knockdown or pharmacological inhibition of mTORC1 signaling suppressed NB-induced NIH3T3 cell transformation. Furthermore, NB enhanced the survival of human Jurkat T-ALL cells by inactivating the pro-apoptotic protein BCL2-associated agonist of cell death (BAD).
CONCLUSION
We demonstrated the pivotal role of NB in cell transformation and survival and identified PIM1as a key downstream target of NB. These findings propose a promising therapeutic strategy for patients with NB fusion-positive leukemia.
Topics: Humans; Proto-Oncogene Proteins c-pim-1; Animals; Mice; Cell Transformation, Neoplastic; Nuclear Pore Complex Proteins; Oncogene Proteins, Fusion; Jurkat Cells; Up-Regulation; NIH 3T3 Cells; Proto-Oncogene Mas; Transcription Factors; Apoptosis; Cell Proliferation
PubMed: 38940430
DOI: 10.1002/cam4.7445