Oncogenic Research Articles

DNA methylation patterns are influenced by Pax3::Foxo1 expression and developmental lineage in rhabdomyosarcoma tumours forming in genetically engineered mouse models.

Rhabdomyosarcoma (RMS) is a family of phenotypically myogenic paediatric cancers consisting of two major subtypes: fusion-positive (FP) RMS, most commonly involving the PAX3::FOXO1 fusion gene, formed by the fusion of paired box 3 (PAX3) and forkhead box O1 (FOXO1) genes, and fusion-negative (FN) RMS, lacking these gene fusions. In humans, DNA methylation patterns distinguish these two subtypes as well as mutation-associated subsets within these subtypes. To investigate the biological factors responsible for these methylation differences, we profiled DNA methylation in RMS tumours derived from genetically engineered mouse models (GEMMs) in which various driver mutations were introduced into different myogenic lineages. Our unsupervised analyses of DNA methylation patterns in these GEMM tumours yielded two major clusters, corresponding to high and no/low expression of Pax3::Foxo1, which mirrored the results for human FP and FN RMS tumours. Two distinct methylation-defined subsets were found for GEMM RMS tumours with no/low Pax3::Foxo1 expression: one subset enriched in Pax7 lineage tumours and a second subset enriched in myogenic factor 5 (Myf5) lineage tumours. Integrative analysis of DNA methylation and transcriptomic data in mouse and human RMS revealed a common group of differentially methylated and differentially expressed genes, highlighting a conserved set of genes functioning in both human RMS models and GEMMs of RMS. In conclusion, these studies provide insight into the roles of oncogenic fusion proteins and developmental lineages in establishing DNA methylation patterns in FP and FN RMS respectively. © 2025 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Monophthalates of betulinic acid and related pentacyclic triterpenes inhibit efficiently the SOS-mediated nucleotide exchange and impact PI3K/AKT signaling in oncogenic K-RAS4B proteins.

Betulinic acid and other herbal pentacyclic triterpenes have attracted interest in cancer research as these natural products induce apoptosis and suppress tumor progression. However, the molecular basis of the antitumor effect is still unknown. Here we show that monophthalates of betulinic acid and related triterpenes inhibit GDP/GTP exchange in oncogenic K-RAS4B proteins via the PI3K/AKT downstream cascade. According to a binding model based on molecular modelling, these derivatives act like a molecular glue that stabilizes an unproductive K-RAS4Ballo:SOS complex. This represents a new mode of action and could be an attractive route for targeting RAS-related cancers.

Enhanced antitumor immunity in breast cancer: Synergistic effects of ADAM10/ADAM17 inhibition, metabolic modulation, and camptothecin-loaded selenium nanoparticles.

In this study, we investigate the impact of a multi-targeted therapeutic approach that includes camptothecin (CPT), a potent chemotherapeutic topoisomerase inhibitor; metformin (Met), a metabolic modulator with emerging anti-tumor effects; and GW280264X, an inhibitor of ADAM 10/ADAM 17 enzymes, which are associated with tumor invasion and immune response. The study aims to assess the combined effects of these agents in enhancing CD8+ T cell-mediated anti-tumor immunity and suppressing cancer cell growth in triple-negative breast cancer (TNBC) models, both in vitro and in vivo. Cell viability was performed on the 4T1 human TNBC cell line. Furthermore, we examined c-MYC protein expression by western blot, TOX and NR4A expression by Real-time PCR, and the number of CD8+ CD28+ T cells by immunofluorescence assay to demonstrate the anticancer effects of combined of CPT, Met and GW280264X in BC growth, exhaustion and senescence of T cells. Regarding cell viability, HA-Se@CPT+Met and HA-Se@CPT+Met+GW280264X treatments decreased 4T1 cell growth (p<0.001). Combination therapy of Met, HA-Se@CPT, and GW280264X significantly reduced tumor volume and weight in vivo. This treatment also increased the number of CD8+ CD28+ T cells in the tumor microenvironment (TME) of BC (p<0.0001) and decreased the expression of TOX and NR4A (p<0.0001, p<0.01). Furthermore, decreased expression of c-MYC as an oncogene protein was seen in the single and combined treatment by HA-Se@CPT and GW280264X (p<0.05). These findings suggest that of HA-Se@CPT, Met, and GW280264X may inhibit tumor progression in BC by improving the function and infiltration of CD8+ T cells. Their effect is more pronounced when used in combination.

Functional Analysis and Experimental Validation of the Prognostic and Immune Effects of the Oncogenic Protein CDC45 in Breast Cancer.

Cell division cycle protein 45 (CDC45) plays a crucial role in DNA replication. This study investigates its role in breast cancer (BC) and its impact on tumor progression. We utilized the GEO database to screen differentially expressed genes (DEGs) and conducted enrichment analysis on these genes. We established a Nomogram model based on CDC45 and other clinical indicators. Additionally, we performed protein-protein interaction (PPI) network construction, drug sensitivity analysis, and immune correlation analysis of CDC45. The function of CDC45 was further verified through cell and animal experiments. CDC45 is highly expressed in most tumors, including BC. The expression level of CDC45 was significantly associated with age, sex, race, cancer stage, and molecular subtypes (all p < 0.05). CDC45 was incorporated into a Nomogram model, which showed moderate accuracy in predicting patient prognosis. We also analyzed the co-expression genes of CDC45, including TOPBP1, GINS2, MCM5, GINS1, GINS4, POLE2, MCM2, MCM6, MCM4, and MCM7. Furthermore, CDC45 expression was closely linked to immune infiltration levels, immune checkpoint inhibitors, and the therapeutic response to small molecule drugs. Finally, both in vitro and in vivo experiments confirmed the cancer-promoting effect of CDC45 in BC. The expression level of CDC45 is linked to the prognosis, immune infiltration, and drug sensitivity of BC. In vitro and in vivo experiments have confirmed that CDC45 acts as a cancer-promoting protein in breast cancer.

Liposomes-mediated enhanced antitumor effect of docetaxel with BRD4-PROTAC as synergist for breast cancer chemotherapy/immunotherapy.

It has been reported that proteolysis-targeting chimeras (PROTACs) can effectively degrade intracellular oncogenic proteins, providing an ideal strategy for cancer treatment. ARV825, a bromodomain-containing protein 4 (BRD4)-PROTAC, has demonstrated the capacity to enhance the antitumor effect of the classic chemotherapeutic agent docetaxel (DTX). However, there are three major challenges to the broader in vivo application of ARV825: poor solubility, poor permeability, and off-target effects. Additionally, the efficient co-delivery of ARV825 and DTX to tumor tissues for a synergistic therapeutic effect remains unresolved. In this study, liposomes were utilized as co-delivery vehicles for ARV825 and DTX to effectively address these issues. The well-established liposomes significantly improved the solubility of both ARV825 and DTX while maintaining a sustained release profile in blood-mimetic conditions. The co-loaded liposomes accumulated in tumor tissues via the enhanced permeability and retention (EPR) effect. After internalization, ARV825 effectively degraded intracellular BRD4 proteins and downregulated the expression of both Bcl-2 and PD-L1 proteins, thereby increasing tumor cell apoptosis and enhancing the tumor immune response. This, in turn, augmented the antitumor effect of DTX in vivo without undesired side effects. In conclusion, BRD4-PROTAC may serve as a promising synergistic agent alongside the conventional chemotherapeutic agent DTX, with liposomes functioning as effective co-delivery vehicles.

Bioinformatic investigation of Lytechinus variegatus coelomic fluid peptides as multiple oncogenic proteins inhibitors of colorectal cancer

Context: Colorectal cancer (CRC) remains a significant global health challenge despite advances in treatment modalities. The coelomic fluid of Lytechinus variegatus emerges as a rich source of bioactive peptides with the potential as a new therapeutic anticancer agent. Aims: To analyze the toxicity, allergenicity, and potential of L. variegatus coelomic fluid peptides as multitarget inhibitor agents of CRC cancer cells through an in silico study. Methods: Ten peptides from L. variegatus coelomic fluid were processed using UCSF Chimera software to model the three-dimensional structure. ToxinPred and AllerTop web servers were used to analyze the toxicity and allergenicity of peptides, respectively. The 3D structures of EGFR, AKT1, GSK3B, VEGFR2, and JAK3 were retrieved from the PDBJ database. MOE Software was used to perform molecular docking. Results: Peptide 4 binds to the ATP binding pocket of GSK3B protein with the strongest binding affinity value (-8,68 kcal/mol). The docking results between EGFR and peptides showed that peptide 10 binds to the ATP binding pocket with the lowest binding affinity (-9.52 kcal/mol). Peptide 2 binds to the ATP binding pocket of AKT1 with the lowest binding affinity value (-9.16 kcal/mol). Peptide 3 has the lowest binding affinity value of the JAK3 ATP binding pocket (-8,67 kcal/mol). Peptide 7 binds to the ATP binding pocket of VEGFR2 with the strongest binding affinity (-9,67 kcal/mol). Conclusions: The L. variegatus peptides have the potential as multitarget anti-CRC agents by inhibiting the activity of GSK3B, EGFR, AKT1, JAK3, and VEGFR2 proteins through the ATP competitive inhibitor action based on in silico study.

Targeting Oncogenic RET Kinase by Simultaneously Inhibiting Kinase Activity and Degrading the Protein.

The rearranged-during-transfection (RET) kinase is a validated target for the treatment of RET-altered cancers. Currently approved RET-selective kinase inhibitors, selpercatinib (LOXO-292) and pralsetinib (BLU-667), increase the oncogenic RET protein level upon treatment, which may affect their efficacy. We seek to reduce the oncogenic RET protein level and RET kinase activity simultaneously. Here, we report the development of proteolysis targeting chimera (PROTAC) degraders of oncogenic RET protein. Compound YW-N-7 exhibited dual action of selectively inhibiting and depleting RET protein both in vitro and in vivo. Proteomic analysis indicated that YW-N-7 is highly specific to RET. In cell cultures, reducing RET fusion protein potentiated the activity of LOXO-292. Furthermore, YW-N-7 showed significant activity in inhibiting KIF5B-RET-driven xenograft tumors in animals. This study exemplifies the feasibility of simultaneously inhibiting and degrading oncogenic RET kinase for cancer therapy.

Epigenetic Therapies.

Epigenetic therapies are emerging for pediatric cancers. Due to the relatively low mutational burden in pediatric tumors, epigenetic dysregulation and differentiation blockade is a hallmark of oncogenesis in some childhood cancers. By targeting epigenetic regulators that maintain tumor cells in a primitive developmental state, epigenetic therapies may induce differentiation. The most well-studied and clinically advanced epigenetic-targeted therapies include azacitidine and decitabine, which inhibit DNA methylation through competitive inhibition of the enzymatic activity of the DNA methyltransferase family enzymes. These DNA hypomethylating agents are Food and Drug Administration (FDA) approved for hematologic malignancies. The discovery that DNA hypermethylation occurs in patients with isocitrate dehydrogenase (IDH) mutations has led to the development and FDA approval of IDH inhibitors for hematologic and solid tumors. Epigenetic dysregulation in pediatric tumors is also driven by changes in the "histone code" that either promote oncogene expression or repress tumor suppressors. Cancers whose chromatin landscape is characterized by such aberrant histone posttranslational modifications may be amenable to targeted therapies that inhibit the chromatin-modifying enzymes that read, write, and erase these histone modifications. Small molecules that inhibit the enzymatic activity of histone deacetylases, acetyltransferases, and methyltransferases have been approved for the treatment of some adult cancers, and these agents are currently under investigation in various pediatric tumors. Chromatin regulatory complexes can be hijacked by oncogenic fusion proteins that are produced by chromosomal translocations, which are common drivers in pediatric cancer. Small molecules that disrupt oncogenic fusion protein activity and their associated chromatin complexes have demonstrated remarkable promise, and this approach has become the standard treatment for a subset of leukemias driven by the PML-RARA oncogenic fusion protein. A deeper understanding of the mechanisms that drive epigenetic dysregulation in pediatric cancer may hold the key to future success in this field, as the landscape of druggable epigenetic targets is also expanding.

MYO1F regulates T-cell activation and glycolytic metabolism by promoting the acetylation of GAPDH.

Proper cellular metabolism in T cells is critical for a productive immune response. However, when dysregulated by intrinsic or extrinsic metabolic factors, T cells may contribute to a wide spectrum of diseases, such as cancers and autoimmune diseases. However, the metabolic regulation of T cells remains incompletely understood. Here, we show that MYO1F is required for human and mouse T-cell activation after TCR stimulation and that T-cell-specific Myo1f knockout mice exhibit an increased tumor burden and attenuated EAE severity due to impaired T-cell activation in vivo. Mechanistically, after TCR stimulation, MYO1F is phosphorylated by LCK at tyrosines 607 and 634, which is critical for glyceraldehyde-3-phosphate dehydrogenase (GAPDH) acetylation at Lys84, 86 and 227 mediated by α-TAT1, which is an acetyltransferase, and these processes are important for its activation, cellular glycolysis and thus the effector function of T cells. Importantly, we show that a fusion protein of VAV1-MYO1F, a recurrent peripheral T-cell lymphoma (PTCL)-associated oncogenic protein, promotes hyperacetylation of GAPDH and its activation, which leads to aberrant glycolysis and T-cell proliferation, and that inhibition of the activity of GAPDH significantly limits T-cell activation and proliferation and extends the survival of hVAV1-MYO1F knock-in mice. Moreover, hyperacetylation of GAPDH was confirmed in human PTCL patient samples containing the VAV1-MYO1F gene fusion. Overall, this study revealed not only the mechanisms by which MYO1F regulates T-cell metabolism and VAV1-MYO1F fusion-induced PTCL but also promising therapeutic targets for the treatment of PTCL.

The mechanism of sevoflurane affecting ovarian cancer cell proliferation and migration by regulating RNA methylase TRDMT1 to activate the β-catenin pathway

ObjectiveSevoflurane (Sevo), a commonly used inhalant anesthetic clinically, is associated with a worsened cancer prognosis, and we investigated its effect on RNA methylase tRNA aspartic acid methyltransferase 1 (TRDMT1) expression and ovarian cancer (OC) cell malignant phenotypes.MethodsHuman OC cells (OVCAR3/SKOV3) were pretreated with 3.6% Sevo and cultured under normal conditions for 48 h, with their viability assessed. After 2-h Sevo treatment or interference plasmid transfections to down-regulate TRDMT1/adenomatous polyposis coli (APC), changes in TRDMT1, APC and β-catenin expression, cell proliferative activity, cycle, apoptosis, migration, invasion, and 5-methylcytosine (m5C) methylation potential modification sites were evaluated. Additionally, APC mRNA m5C methylation level and stability, the binding of APC mRNA with TRDMT1, the binding intensity of APC and β-catenin, and β-catenin nuclear translocation were detected Lastly, Cyclin D1, cellular-myelocytomatosis viral oncogene (C-myc) and β-catenin protein levels, and ki67-positive rate were assessed.ResultsSevo treatment boosted cell cycle, proliferation, migration and invasion, suppressed apoptosis and APC expression, and up-regulated C-myc, β-catenin, TRDMT1 and Cyclin D1 levels. Silencing TRDMT1 or β-catenin partially averted Sevo-mediated promotion effects on cell malignant biological behaviors. Lowly-expressed APC annulled the effect of silencing TRDMT1 and promoted cell malignant behaviors. Sevo enhanced APC mRNA m5C modification and degradation and activated the APC/β-catenin pathway by increasing TRDMT1, thus encouraging OC growth in vivo.ConclusionsSevo stimulated APC m5C modification and curbed its expression by up-regulating TRDMT1, which in turn activated the β-catenin pathway to stimulate OC cell cycle, invasion, proliferation, and migration and to suppress apoptosis.Graphical abstract

LYRM2 Promotes the Growth and Metastasis of Hepatocellular Carcinoma via Enhancing HIF-1α-Dependent Glucose Metabolic Reprogramming.

Hepatocellular carcinoma (HCC) is a foetal malignancy with dismal overall survival. The molecular mechanism underlying the progression of HCC remain largely unknown. LYR motif containing 2 (LYRM2) has been identified as an oncogene in colorectal cancer; however, its expression, functions and molecular mechanism in the context of HCC has not been investigated. Data derived from The Cancer Gemome Atlas, along with findings from our patients' cohort, indicate that LYRM2 expression is elevated in HCC tissues and correlates with adverse clinicopathological features and prognosis in HCC patients. Subsequent research into the biological functions of LYRM2 has revealed that it promotes the proliferation, migration, invasion and epithelial-mesenchymal transition of HCC cells, both invitro and invivo. Mechanistic insights have shown that LYRM2 interacts with HIF-1α, enhancing the protein stability of HIF-1α, which in turn increases cellular glycolysis and inhibits mitochondrial respiration. Moreover, the glucose metabolic reprogramming mediated by LYRM2 is implicated in its role in promoting HCC growth and metastasis. Collectively, this study identifies that LYRM2 as a novel oncogenic protein in HCC and elucidates its contribution to HCC progression through enhancing HIF-1α-dependent glucose metabolic reprogramming.

Human papillomaviruses: origin, oncogenic factors and markers for cervical cancer screening

The Human papillomaviruses (HPV) have existed in the human population since the archaic hominids. Over the course of human migration and evolution, HPVs have co-evolved with humans on all continents to become today the leading cause of cervical cancer. HPVs are classified by genera, species, genotype, lineage, sub-lineage and variants. Among more than 200 HPV genotypes, HPV16 is the most common and the most oncogenic at high-risk (HPV-HR). If viral oncogenesis is governed by numerous factors and mechanisms involving the virus and its host, the E6/E7 oncogenic proteins of HR-HPV play a central role and are always expressed in cervical cancers. Those of HPV16 have the greatest affinity for cellular proteins involved in cellular control, p53/E6 and pRb/E7. Some E6/E7 HPV16 mutants are associated with persistent infection, correlating with viral lineages and their ethnic and geographical origin. If the splicing of viral mRNAs encoding E6/E7 allows the overexpression of the E7 protein, which is an essential condition for the establishment of HR-HPV oncogenesis, other mechanisms contribute to strengthening it. On the one hand, the accidental integration of the viral genome, in particular the E1/E2 coding region, participates in the transformation of the infected cell. On the other hand, hypermethylation of the viral L1/L2 genomic regions is observed in the advanced stages of infection. Different methods for analyzing mutations, splice sites, integrations and methylations of the viral genome have been described. These virological markers could complete the detection of HR-HPV in the context of cervical cancer screening, currently recommended in France.

Protacs in cancer therapy: mechanisms, design, clinical trials, and future directions.

Cancer develops as a result of changes in both genetic and epigenetic mechanisms, which lead to the activation of oncogenes and the suppression of tumor suppressor genes. Despite advancements in cancer treatments, the primary approach still involves a combination of chemotherapy, radiotherapy, and surgery, typically providing a median survival of approximately five years for patients. Unfortunately, these therapeutic interventions often bring about substantial side effects and toxicities, significantly impacting the overall quality of life for individuals undergoing treatment. Therefore, urgent need of research required which comes up with effective treatment of cancer. This review explores the transformative role of Proteolysis-Targeting Chimeras (PROTACs) in cancer therapy. PROTACs, an innovative drug development strategy, utilize the cell's protein degradation machinery to selectively eliminate disease-causing proteins. The review covers the historical background, mechanism of action, design, and structure of PROTACs, emphasizing their precision in targeting oncogenic proteins. The discussion extends to the challenges, nanotechnology applications, and ongoing clinical trials, showcasing promising results and clinical progress. The review concludes with insights into patents, future directions, and the potential impact of PROTACs in addressing dysregulated protein expression across various diseases. Overall, it provides a concise yet comprehensive overview for researchers, clinicians, and industry professionals involved in developing targeted therapies.

Microtubule Association of EML4-ALK V3 Is Key for the Elongated Cell Morphology and Enhanced Migration Observed in V3 Cells.

The EML4-ALK oncogene drives tumour progression in approximately 5% of cases of non-small-cell lung cancers. At least 15 EML4-ALK variants have been identified, which elicit differential responses to conventional ALK inhibitors. Unfortunately, most, if not all, patients eventually acquire resistance to these inhibitors and succumb to the disease, which warrants the need for alternative targets to be identified. The most aggressive variant, EML4-ALK variant 3 (V3), assembles into a complex on interphase microtubules together with the NEK9 and NEK7 kinases, which leads to the downstream phosphorylation of NEK7 substrates. Overall, this promotes an elongated cell morphology and an enhanced migratory phenotype, which likely contributes to the increased metastasis often seen in V3 patients. Here, using two separate approaches to displace V3 from microtubules and a variety of in vitro assays, we show that microtubule association of EML4-ALK V3 is required for both V3 phenotypes, as removal of the oncogenic fusion protein from microtubules led to the dissociation of the V3-NEK9-NEK7 complex and the reversal of both phenotypic changes. Overall, we propose that targeting the interaction between EML4-ALK V3 and microtubules might offer a novel therapeutic option, independent of ALK activity, for V3+ NSCLC patients with acquired resistance to ALK inhibitors.

Recent Trends in Development of Novel Therapeutics for Modulation of 14-3-3 Protein-Protein Interactions in Diseases.

14-3-3s constitute a group of proteins belonging to the phosphoserine/phosphothreonine family that are involved in the regulation of several physiological pathways by interacting with several client proteins. All the eukaryotic cells are known to possess 14-3-3 isoforms. In addition, 14-3-3s isolated from different eukaryotic cells share high sequence homology with each other. Seven isoforms (β, γ, ε, η, ζ, σ, and τ/θ) have been yet identified in mammals. These proteins participate in several physiological processes by either stimulating or interfering with the enzymatic activities of binding partners. These proteins take part in several human diseases upon dysregulation which include cancer and neurodegenerative disorders. Recently, a number of evidences suggest that the interaction of 14-3-3s with either oncogenic or pro-apoptotic proteins can lead to cancer development in animals. In the case of neurodegenerative disorders, 14-3-3s interact with Lewy bodies and neurofibrillary tangles in Parkinson's and Alzheimer's diseases, respectively. The current review focuses on strategies to regulate 14-3-3s' proteins in diseases. Potential strategies to regulate 14-3-3 interactions in disease conditions include the use of small interfering RNAs (siRNA), microRNA (miRNA), and modifications of 14-3-3s or their client proteins. In addition, some peptides or chemicals can also serve as potential inhibitors of 14-3-3. However, optimization of these therapeutic strategies is required for their practical implementations.

A Rare Case of an Infant With TFE3 Mutation Presenting With Direct Hyperbilirubinemia and Hepatomegaly.

Translocations within the TFE gene resulting in oncogenic fusion proteins have been associated with multiple neoplasms. De novo mutations in the X-linked gene TFE3 in exons 3 and 4 are considered to contribute to lysosomal storage disorder-like features. However, the histologic findings within the livers of patients with TFE3 mutations are not well characterized. The authors report a case of a 12 day old term male who was admitted to the pediatric intensive care unit and went on to develop worsening direct hyperbilirubinemia and hepatomegaly. Due to the constellation of clinical findings, whole genome sequencing was performed and a rare de novo hemizygous mutation was identified in the TFE3 gene (c.560C > T; p.Thr187Met) which was thought to be likely pathogenic. The patient subsequently had 2 liver biopsies performed, both with similar histologic findings. The liver was found to have a giant cell hepatitis pattern of injury with severe cholestasis and extensive pseudorosette formation. Additional studies are needed to understand the histologic changes which could be associated with mutations in the TFE3 gene. The impact of a TFE3 mutation on the liver represents an area where further study is necessary to provide prognostic and therapeutic guidance for future patients.

Epichaperome Inhibition by PU-H71-Mediated Targeting of HSP90 Sensitizes Glioblastoma Cells to Alkylator-Induced DNA Damage.

Targeted therapies have been largely ineffective against glioblastoma (GBM) owing to the tumor's heterogeneity and intrinsic and adaptive treatment resistance. Targeting multiple pro-survival pathways simultaneously may overcome these limitations and yield effective treatments. Heat shock protein 90 (HSP90), an essential component of the epichaperome complex, is critical for the proper folding and activation of several pro-survival oncogenic proteins that drive GBM biology. Using a panel of biochemical and biological assays, we assessed the expression of HSP90 and its downstream targets and the effects of PU-H71, a highly specific and potent HSP90 inhibitor, on target modulation, downstream biochemical alterations, cell cycle progression, proliferation, migration, and apoptosis in patient-derived glioma stem-like cells (GSCs) with molecular profiles characteristic of GBM, as well as commercial glioma cell lines and normal human astrocytes (NHAs). HSP90 inhibition by PU-H71 in GSCs significantly reduced cell proliferation, colony formation, wound healing, migration, and angiogenesis. In glioma cells, but not NHAs, potent PU-H71-mediated HSP90 inhibition resulted in the downregulation of pro-survival client proteins such as EGFR, MAPK, AKT, and S6. This reduction in pro-survival signals increased glioma cells' sensitivity to temozolomide, a monofunctional alkylator, and the combination of PU-H71 and temozolomide had greater anticancer efficacy than either agent alone. These results confirm that HSP90 is a strong pro-survival factor in molecularly heterogeneous gliomas and suggest that epichaperome inhibition with HSP90 inhibitors warrants further investigation for the treatment of gliomas.

PROTAC and Molecular Glue Degraders of the Oncogenic RNA Binding Protein Lin28.

The interaction between proteins and RNA is crucial for regulating gene expression, with dysregulation often linked to diseases such as cancer. The RNA-binding protein (RBP) Lin28 inhibits the tumor suppressor microRNA (miRNA)let-7, making it a significant oncogenic factor in tumor progression and metastasis. In this study, a small molecule is used that binds Lin28 and blocks its inhibition of let-7. To enhance its efficay, the inhibitor is transformed into degraders via two degradation approaches: Proteolysis Targeting Chimera (PROTAC) and molecular glue. A series of PROTAC bifunctional molecules and molecular glues capable of degrading Lin28 in cells.is developed Both strategies significantly reduce overexpressed Lin28 and alleviate cancer cellular phenotypes. Notably, the molecular glue approach demonstrates exceptional potency, surpassing PROTAC in several aspects. This outcome underscores the superior efficiency of the molecular glue approach for targeted Lin28 degradation and highlights its potential for addressing associated diseases with small molecules. Innovative small molecule strategies such as molecular glue and PROTAC technology for targeted RBP degradation, hold promise for opening new avenues in RNA modulation and addressing related diseases.

Targeting eIF4G1-dependent translation in melanoma.

Elevated expression of components of eIF4F translation initiation complex has been documented in cancer, resulting in enhanced translation of mRNAs encoding pro-tumorigenic factors, including oncogenic proteins. We previously identified SBI-756, a small molecule that interferes with the eIF4F assembly and overcomes melanoma resistance to BRAF inhibitors. SBI-756 enhanced anti-tumor immunity in pancreatic cancer and was effective in the treatment of diffuse large B cell lymphoma. Here, we identified the eIF4G1 MA3 (4G1-MA3) domain as the target of SBI-756, attenuating eIF4F complex assembly. Melanoma cells expressing a mutant form of 4G1-MA3 exhibited polysome profiles resembling those of melanoma cells treated with SBI-756. A structure-based in silico screen against the eIF4G1 MA3 domain identified M19, a small molecule inhibitor that exhibited anti-melanoma effects. RNA sequencing (RNA-seq) revealed upregulation of UPR, mTOR, p53, and ROS signaling in M19-treated melanoma cells. Ribosome sequencing identified changes in ribosomal structure and electron transport chain components following M19-6 treatment of melanoma cells. Autophagy and histone deacetylase inhibitors were found to enhance anti-neoplastic activities of M19 or its analog, M19-6. M19-6 conferred a greater effect on melanoma than melanocytes and overcame melanoma resistance to BRAF or MEK inhibitors. Alone, M19-6 reduced melanoma growth and metastasis in a xenograft model. M19-6 offers a new therapeutic modality to overcome resistance and metastasis.

CIP2A inhibitors TD52 and Ethoxysanguinarine promote macrophage autophagy and alleviates acute pancreatitis by modulating the AKT-mTOR pathway

BackgroundAcute pancreatitis (AP) is a prevalent and serious condition within the digestive system, with approximately 20 % to 30 % of cases advancing to severe acute pancreatitis (SAP). During the initial phases of SAP, macrophages are activated in response to the substantial amounts of acinar cell contents and damage-associated molecular patterns (DAMPs) resulting from acinar cell destruction. Subsequently, activated macrophages release a significant array of pro-inflammatory factors that exacerbate the progression of SAP. Cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic protein that is intimately linked to immune regulation. While the role of CIP2A in T-cell-mediated specific immune responses has been reported, its function and mechanism in macrophages, a component of non-specific immunity, have not been widely studied. This research fills this knowledge gap by elucidating the critical role of CIP2A in regulating macrophage autophagy and inflammation. This finding not only expands our understanding of CIP2A in immune modulation but also provides a new scientific basis and potential application prospects for targeting CIP2A in the treatment of AP. MethodsWe established AP using a combination of palmitoleic acid with anhydrous ethanol or using caerulein alone. The effects of TD52 and Ethoxysanguinarine (Etho) on SAP were evaluated through serological, histopathological, and tissue inflammation observations. The effect of TD52 on macrophage activation in vitro was examined using primary macrophages (PMs) and RAW264.7 cells. ResultsWe found that TD52 and Etho inhibit CIP2A expression while reducing the levels of serum amylase, lipase, and inflammatory cytokines, thereby alleviating the pathological symptoms of SAP. Additionally, TD52 could reduce the infiltration of macrophages into pancreatic tissue. Therefore, we established a model of macrophage inflammatory response mimicking the pathophysiological process of AP and detected changes in inflammation, apoptosis, and autophagy through pre-treatment of macrophages with TD52. The results show that inhibiting CIP2A expression decreases the release of inflammatory cytokines and reduces apoptosis in macrophages. Further exploration revealed that TD52 promoted macrophage autophagy regulation and inhibited the AKT-mTOR pathway to modulate macrophage activation. ConclusionIn summary, our findings indicate that TD52 and Etho can alleviate the severity of SAP. TD52 can block the AKT-mTOR pathway to promote macrophage autophagy, thereby improving SAP. Thus, CIP2A may serve as one of the molecular targets in SAP, highlighting its potential as a therapeutic option.