Seleno-amino Acid Metabolism Reshapes the Tumor Microenvironment: from Cytotoxicity to Immunotherapy.

Selenium (Se) is an essential trace element for biological processes. Seleno-amino acids (Se-AAs), known as the organic forms of Se, and their metabolic reprogramming have been increasingly recognized to regulate antioxidant defense, enzyme activity, and tumorigenesis. Therefore, there is emerging interest in exploring the potential application of Se-AAs in antitumor therapy. In addition to playing a vital role in inhibiting tumor growth, accumulating evidence has revealed that Se-AA metabolism could reshape the tumor microenvironment (TME) and enhance immunotherapy responses. This review presents a comprehensive overview of the current progress in multifunctional Se-AAs for antitumor treatment, with a particular emphasis on elucidating the crosstalk between Se-AA metabolism and various cell types in the TME, including tumor cells, T cells, macrophages, and natural killer cells. Furthermore, novel applications integrating Se-AAs are also discussed alongside prospects to provide new insights into this emerging field.

Integrating single-cell and spatial analysis reveals MUC1-mediated cellular crosstalk in mucinous colorectal adenocarcinoma.

BACKGROUND: Mucinous colorectal adenocarcinoma (MCA) is a distinct subtype of colorectal cancer (CRC) with the most aggressive pattern, but effective treatment of MCA remains a challenge due to its vague pathological characteristics. An in-depth understanding of transcriptional dynamics at the cellular level is critical for developing specialised MCA treatment strategies. METHODS: We integrated single-cell RNA sequencing and spatial transcriptomics data to systematically profile the MCA tumor microenvironment (TME), particularly the interactome of stromal and immune cells. In addition, a three-dimensional bioprinting technique, canonical ex vivo co-culture system, and immunofluorescence staining were further applied to validate the cellular communication networks within the TME. RESULTS: This study identified the crucial intercellular interactions that engaged in MCA pathogenesis. We found the increased infiltration of FGF7+/THBS1+ myofibroblasts in MCA tissues with decreased expression of genes associated with leukocyte-mediated immunity and T cell activation, suggesting a crucial role of these cells in regulating the immunosuppressive TME. In addition, MS4A4A+ macrophages that exhibit M2-phenotype were enriched in the tumoral niche and high expression of MS4A4A+ was associated with poor prognosis in the cohort data. The ligand-receptor-based intercellular communication analysis revealed the tight interaction of MUC1+ malignant cells and ZEB1+ endothelial cells, providing mechanistic information for MCA angiogenesis and molecular targets for subsequent translational applications. CONCLUSIONS: Our study provides novel insights into communications among tumour cells with stromal and immune cells that are significantly enriched in the TME during MCA progression, presenting potential prognostic biomarkers and therapeutic strategies for MCA. KEY POINTS: Tumour microenvironment profiling of MCA is developed. MUC1+ tumour cells interplay with FGF7+/THBS1+ myofibroblasts to promote MCA development. MS4A4A+ macrophages exhibit M2 phenotype in MCA. ZEB1+ endotheliocytes engage in EndMT process in MCA.

Comparison of lactic and propionic acid hydrolysis for production of xylo-oligosaccharides and ethanol from polysaccharides in Toona sinensis branch.

Xylan-type hemicellulose hydrolysis by an organic acid solution for the production of xylo-oligosaccharides (XOS) is efficient and eco-friendly, but the effects of different organic acids on XOS production from Toona sinensis branch (TB) biomass is limited. In this work, under the conditions of 170 °C for 60 min, 33.1 % and 38.7 % XOS yields were obtained from polysaccharides present in TB by 2 % lactic acid (LA) and 6 % propionic acid (PA), respectively. Then 77 % of the lignin was removed by hydrogen peroxide-acetic acid pretreatment system, and 39.5 % and 44.7 % XOS yield were obtained from polysaccharides in delignification TB by 2 % LA and 6 % PA, respectively. It was found that PA hydrolysis, especially from delignified TB, resulted in higher XOS yield and purity compared to LA hydrolysis. Moreover, the content of byproducts (xylose, hydroxymethyl-furfural and furfural) in PA hydrolysate was lower. Following the hydrolysis process, the simultaneous saccharification and fermentation of the TB solid residue achieved an ethanol yield of 71.5 %. This work proposed an integrated process to preferentially convert the TB hemicellulose into valuable XOS and then convert the cellulose into ethanol. This process had the advantages of eliminating the need for isolation and purification of xylan, and the potential to obtain multiple products from the same raw material.

A rare morphology of the cardiac fibroma in a child: a case report.

Here we report a rare morphology of a cardiac fibroma in a child. A 2-year and 8-month-old toddler came for "chronic constipation" and was found to have a heart murmur on cardiac auscultation. Further transthoracic echocardiography suggested "a strong echogenic mass in the left ventricular wall, with some part of "a string of beads" in shape extending into left ventricle outflow tract", which was atypical for either a tumor, thrombus or vegetation. The child underwent resection of the mass and mitral valvuloplasty. Pathological examination confirmed the mass as a cardiac fibroma.

An optimization framework for large-scale screening under limited testing capacity with application to COVID-19.

We consider the problem of targeted mass screening of heterogeneous populations under limited testing capacity. Mass screening is an essential tool that arises in various settings, e.g., ensuring a safe supply of blood, reducing prevalence of sexually transmitted diseases, and mitigating the spread of infectious disease outbreaks. The goal of mass screening is to classify whole population groups as positive or negative for an infectious disease as efficiently and accurately as possible. Under limited testing capacity, it is not possible to screen the entire population and hence administrators must reserve testing and target those among the population that are most in need or most susceptible. This paper addresses this decision problem by taking advantage of accessible population-level risk information to identify the optimal set of sub-populations to target for screening. We conduct a comprehensive analysis that considers the two most commonly adopted schemes: Individual testing and Dorfman group testing. For both schemes, we formulate an optimization model that aims to minimize the number of misclassifications under a testing capacity constraint. By analyzing the formulations, we establish key structural properties which we use to construct efficient and accurate solution techniques. We conduct a case study on COVID-19 in the United States using geographic-based data. Our results reveal that the considered proactive targeted schemes outperform commonly adopted practices by substantially reducing misclassifications. Our case study provides important managerial insights with regards to optimal allocation of tests, testing designs, and protocols that dictate the optimality of schemes. Such insights can inform policy-makers with tailored and implementable data-driven recommendations.

In Silico Discovery of Stapled Peptide Inhibitor Targeting the Nur77-PPARγ Interaction and Its Anti-Breast-Cancer Efficacy.

The binding of peroxisome proliferator-activated receptor γ (PPARγ) to the orphan nuclear receptor Nur77 facilitates the ubiquitination and degradation of Nur77, and leads to aberrant fatty acid uptake for breast cancer progression. Because of its crucial role in clinical prognosis, the interaction between Nur77 and PPARγ is an attractive target for anti-breast-cancer therapy. However, developing an inhibitor of the Nur77-PPARγ interaction poses a technical challenge due to the absence of the crystal structure of PPARγ and its corresponding interactive model with Nur77. Here, ST-CY14, a stapled peptide, is identified as a potent modulator of Nur77 with a KD value of 3.247 × 10-8 M by in silico analysis, rational design, and structural modification. ST-CY14 effectively increases Nur77 protein levels by blocking the Nur77-PPARγ interaction, thereby inhibiting lipid metabolism in breast tumor cells. Notably, ST-CY14 significantly suppresses breast cancer growth and bone metastasis in mice. The findings demonstrate the feasibility of exploiting directly Nur77-PPARγ interaction in breast cancer, and generate what to the best knowledge is the first direct inhibitor of the Nur77-PPARγ interaction available for impeding fatty acid uptake and therapeutic development.

Radiotherapy alone versus concurrent chemoradiotherapy in patients with stage II and T3N0 nasopharyngeal carcinoma with adverse features: A propensity score-matched cohort study.

BACKGROUND AND PURPOSE: Whether concurrent chemoradiotherapy would provide survival benefits in patients with stage II and T3N0 NPC with adverse factors remains unclear in IMRT era. We aimed to assess the value of concurrent chemotherapy compared to IMRT alone in stage II and T3N0 NPC with adverse features. MATERIALS AND METHODS: 287 patients with stage II and T3N0 NPC with adverse factors were retrospectively analyzed, including 98 patients who received IMRT alone (IMRT alone group) and 189 patients who received cisplatin-based concurrent chemotherapy (CCRT group). The possible prognostic factors were balanced using propensity score matching (PSM). Kaplan-Meier analysis was used to evaluate the survival rates, and log-rank tests were employed to compare differences between groups. RESULTS: The median follow-up duration was 90.8 months (interquartile range = 75.6-114.7 months). The IMRT alone and the CCRT group were well matched; however, for all survival-related endpoints, there were no significant differences between them (5-year failure-free survival: 84.3% vs. 82.7%, P value = 0.68; 5-year overall survival: 87.3% vs. 90.6%, P value = 0.11; 5-year distant metastasis-free survival: 92.8% vs. 92.5%, P value = 0.97; 5-year locoregional relapse-free survival: 93.4% vs. 89.9%, P value = 0.30). The incidence of acute toxicities in the IMRT alone group was significantly lower than that in the CCRT group. CONCLUSION: For patients with stage II and T3N0 NPC with adverse features treated using IMRT, no improvement in survival was gained by adding concurrent chemotherapy; however, the occurrence of acute toxicities increased significantly. For those combined with non-single adverse factors, the comprehensive treatment strategy needs further exploration.

Dbl family RhoGEFs in cancer: different roles and targeting strategies.

Small Ras homologous guanosine triphosphatase (Rho GTPase) family proteins are highly associated with tumorigenesis and development. As intrinsic exchange activity regulators of Rho GTPases, Rho guanine nucleotide exchange factors (RhoGEFs) have been demonstrated to be closely involved in tumor development and received increasing attention. They mainly contain two families: the diffuse B-cell lymphoma (Dbl) family and the dedicator of cytokinesis (Dock) family. More and more emphasis has been paid to the Dbl family members for their abnormally high expression in various cancers and their correlation to poor prognosis. In this review, the common and distinctive structures of Dbl family members are discussed, and their roles in cancer are summarized with a focus on Ect2, Tiam1/2, P-Rex1/2, Vav1/2/3, Trio, KALRN, and LARG. Significantly, the strategies targeting Dbl family RhoGEFs are highlighted as novel therapeutic opportunities for cancer.

A defined diet for pre-adult Drosophila melanogaster.

Drosophila melanogaster is unique among animal models because it has a fully defined synthetic diet available to study nutrient-gene interactions. However, use of this diet is limited to adult studies due to impaired larval development and survival. Here, we provide an adjusted formula that reduces the developmental period, restores fat levels, enhances body mass, and fully rescues survivorship without compromise to adult lifespan. To demonstrate an application of this formula, we explored pre-adult diet compositions of therapeutic potential in a model of an inherited metabolic disorder affecting the metabolism of branched-chain amino acids. We reveal rapid, specific, and predictable nutrient effects on the disease state consistent with observations from mouse and patient studies. Together, our diet provides a powerful means with which to examine the interplay between diet and metabolism across all life stages in an animal model.

Impact of occupational noise exposure on the hearing level in hospital staffs: a longitudinal study.

The study aimed to evaluate the impact of occupational noise on hearing loss among healthcare workers using audiometry. A longitudinal study was conducted with a six-month follow-up period in a hospital with 21 participants, divided into high-noise-exposure (HNE) and low-noise-exposure (LNE) groups. Mean noise levels were higher in the HNE group (70.4 ± 4.5 dBA), and hearing loss was measured using pure-tone audiometry at baseline and follow-up. The HNE group had significantly higher mean threshold levels at frequencies of 0.25 kHz, 0.5 kHz, 4.0 kHz, and an average of 0.5, 1, 2, and 4 kHz (all p-values < 0.05) after the follow-up period. After adjusting for confounding factors, the HNE group had significantly higher hearing loss levels at 0.25 kHz, 0.5 kHz, and average frequencies of 0.5, 1, 2, and 4 kHz compared to the LNE group at the second measurement. Occupational noise levels above 65 dBA over six months were found to cause significant threshold changes at frequencies of 0.25 kHz, 0.5 kHz, and an average of 0.5-4.0 kHz. This study highlights the risk of noise-induced hearing loss among healthcare workers and emphasizes the importance of implementing effective hearing conservation programs in the workplace. Regular monitoring and assessment of noise levels and hearing ability, along with proper use of personal protective equipment, are crucial steps in mitigating the impact of occupational noise exposure on the hearing health of healthcare workers.

Ca2+ oscillation in vascular smooth muscle cells control myogenic spontaneous vasomotion and counteract post-ischemic no-reflow.

Ischemic stroke produces the highest adult disability. Despite successful recanalization, no-reflow, or the futile restoration of the cerebral perfusion after ischemia, is a major cause of brain lesion expansion. However, the vascular mechanism underlying this hypoperfusion is largely unknown, and no approach is available to actively promote optimal reperfusion to treat no-reflow. Here, by combining two-photon laser scanning microscopy (2PLSM) and a mouse middle cerebral arteriolar occlusion (MCAO) model, we find myogenic vasomotion deficits correlated with post-ischemic cerebral circulation interruptions and no-reflow. Transient occlusion-induced transient loss of mitochondrial membrane potential (ΔΨm) permanently impairs mitochondria-endoplasmic reticulum (ER) contacts and abolish Ca2+ oscillation in smooth muscle cells (SMCs), the driving force of myogenic spontaneous vasomotion. Furthermore, tethering mitochondria and ER by specific overexpression of ME-Linker in SMCs restores cytosolic Ca2+ homeostasis, remotivates myogenic spontaneous vasomotion, achieves optimal reperfusion, and ameliorates neurological injury. Collectively, the maintaining of arteriolar myogenic vasomotion and mitochondria-ER contacts in SMCs, are of critical importance in preventing post-ischemic no-reflow.

Comprehensive analysis of flavor formation mechanisms in the mechanized preparation Cantonese soy sauce koji using absolute quantitative metabolomics and microbiomics approaches.

Based on the widespread application and under-research of mechanized preparation Cantonese soy sauce koji (MP), absolute quantitative approaches were utilized to systematically analyze the flavor formation mechanism in MP. The results indicated that the enzyme activities increased greatly during MP fermentation, and 4 organic acids, 15 amino acids, and 2 volatiles were identified as significantly different flavor actives. The flavor parameters of MP4 were basically identical to those of MP5. Furthermore, microorganisms were dominated by Staphylococcus, Weissella, and Aspergillus in MP, and their biomass demonstrated an increasing trend. A precise enumeration of microorganisms exposed the inaccuracy of relative quantitative data. Concurrently, Staphylococcus and Aspergillus were positively correlated with numerous enzymes and flavor compounds, and targeted strains for enhancing MP quality. The flavor formation network comprises pathways including carbohydrate metabolism, lipid metabolism and oxidation, and protein degradation and amino acid metabolism. In summary, the fermentation period of MP can be substantially shortened without compromising the product quality. These findings lay the groundwork for refining parameters in modern production processes.

Identifying potential dietary treatments for inherited metabolic disorders using Drosophila nutrigenomics.

Inherited metabolic disorders are a group of genetic conditions that can cause severe neurological impairment and child mortality. Uniquely, these disorders respond to dietary treatment; however, this option remains largely unexplored because of low disorder prevalence and the lack of a suitable paradigm for testing diets. Here, we screened 35 Drosophila amino acid disorder models for disease-diet interactions and found 26 with diet-altered development and/or survival. Using a targeted multi-nutrient array, we examine the interaction in a model of isolated sulfite oxidase deficiency, an infant-lethal disorder. We show that dietary cysteine depletion normalizes their metabolic profile and rescues development, neurophysiology, behavior, and lifelong fly survival, thus providing a basis for further study into the pathogenic mechanisms involved in this disorder. Our work highlights the diet-sensitive nature of metabolic disorders and establishes Drosophila as a valuable tool for nutrigenomic studies for informing potential dietary therapies.

Polarization state tomography technique based on coherent synthesis of polarization state and orthogonal polarization state separation method for comprehensive optical imaging.

Comprehensive optical imaging of the intensity, phase, and birefringent information of the biological sample is important because important physical or pathological changes always accompany the changes in multiple optical parameters. Current studies lack such a metric that can present the comprehensive optical property of the sample in one figure. In this paper, a polarization state synthesis tomography (PoST) method, which is based on the principle of polarization state coherent synthesis and demodulation, is proposed to achieve full-field tomographic imaging of the comprehensive information (i.e., intensity, phase, and birefringence) of the biological sample. In this method, the synthesis of the polarization state is achieved by the time-domain full-field low coherence interferometer, where the polarization states of the sample beam and the reference beam are set to be orthogonal for the synthesis of the polarization state. The synthesis of the polarization state enables two functions of the PoST system: (1) Depth information of the sample can be encoded by the synthesized polarization state because only when the optical path length difference between the two arms is within the coherence length, a new polarization state can be synthesized; (2) Since the scattering coefficient, refractive index and the birefringent property of the sample can modulate the intensity and phase of the sample beam, the synthesized polarization state is sensitive to all these three parameters and can provide the comprehensive optical information of the sample. In this work, the depth-resolved ability and the comprehensive optical imaging metric have been demonstrated by the standard samples and the onion cells, demonstrating the potential application value of this method for further investigation of the important physical or pathological process of the biological tissues.

Transcription factor ATMIN facilitates chemoresistance in nasopharyngeal carcinoma.

Despite that the docectaxel-cisplatin-5-fluorouracil (TPF) induction chemotherapy has greatly improved patients' survival and became the first-line treatment for advanced nasopharyngeal carcinoma (NPC), not all patients could benefit from this therapy. The mechanism underlying the TPF chemoresistance remains unclear. Here, by analyzing gene-expression microarray data and survival of patients who received TPF chemotherapy, we identify transcription factor ATMIN as a chemoresistance gene in response to TPF chemotherapy in NPC. Mass spectrometry and Co-IP assays reveal that USP10 deubiquitinates and stabilizes ATMIN protein, resulting the high-ATMIN expression in NPC. Knockdown of ATMIN suppresses the cell proliferation and facilitates the docetaxel-sensitivity of NPC cells both in vitro and in vivo, while overexpression of ATMIN exerts the opposite effect. Mechanistically, ChIP-seq combined with RNA-seq analysis suggests that ATMIN is associated with the cell death signaling and identifies ten candidate target genes of ATMIN. We further confirm that ATMIN transcriptionally activates the downstream target gene LCK and stabilizes it to facilitate cell proliferation and docetaxel resistance. Taken together, our findings broaden the insight into the molecular mechanism of chemoresistance in NPC, and the USP10-ATMIN-LCK axis provides potential therapeutic targets for the management of NPC.

FvKex2 is required for development, virulence, and mycotoxin production in Fusarium verticillioides.

Fusarium verticillioides is one of the most important fungal pathogens causing maize ear and stalk rots, thereby undermining global food security. Infected seeds are usually unhealthy for consumption due to contamination with fumonisin B1 (FB1) mycotoxin produced by the fungus as a virulence factor. Unveiling the molecular factors that determine fungal development and pathogenesis will help in the control and management of the diseases. Kex2 is a kexin-like Golgi-resident proprotein convertase that is involved in the activation of some important proproteins. Herein, we identified and functionally characterized FvKex2 in relation to F. verticillioides development and virulence by bioinformatics and functional genomics approaches. We found that FvKex2 is required for the fungal normal vegetative growth, because the growth of the ∆Fvkex2 mutant was significantly reduced on culture media compared to the wild-type and complemented strains. The mutant also produced very few conidia with morphologically abnormal shapes when compared with those from the wild type. However, the kexin-like protein was dispensable for the male role in sexual reproduction in F. verticillioides. In contrast, pathogenicity was nearly abolished on wounded maize stalks and sugarcane leaves in the absence of FvKEX2 gene, suggesting an essential role of Fvkex2 in the virulence of F. verticillioides. Furthermore, high-performance liquid chromatography analysis revealed that the ∆Fvkex2 mutant produced a significantly lower level of FB1 mycotoxin compared to the wild-type and complemented strains, consistent with the loss of virulence observed in the mutant. Taken together, our results indicate that FvKex2 is critical for vegetative growth, FB1 biosynthesis, and virulence, but dispensable for sexual reproduction in F. verticillioides. The study presents the kexin-like protein as a potential drug target for the management of the devastating maize ear and stalk rot diseases. Further studies should aim at uncovering the link between FvKex2 activity and FB1 biosynthesis genes. KEY POINTS: •The kexin-like protein FvKex2 contributes significantly to the vegetative growth of Fusarium verticillioides. •The conserved protein is required for fungal conidiation and conidial morphology, but dispensable for sexual reproduction. •Deletion of FvKEX2 greatly attenuates the virulence and mycotoxin production potential of F. verticillioides.

Integrative Multi-Omics Analysis Identifies Transmembrane p24 Trafficking Protein 1 (TMED1) as a Potential Prognostic Marker in Colorectal Cancer.

Several TMED protein family members are overexpressed in malignant tumors and associated with tumor progression. TMED1 belongs to the TMED protein family and is involved in protein vesicular trafficking. However, the expression level and biological role of TMED1 in colorectal cancer (CRC) have yet to be fully elucidated. In this study, the integration of patient survival and multi-omics data (immunohistochemical staining, transcriptomics, and proteomics) revealed that the highly expressed TMED1 was related to the poor prognosis in CRC. Crystal violet staining indicated the cell growth was reduced after knocking down TMED1. Moreover, the flow cytometry results showed that TMED1 knockdown could increase cell apoptosis. The expression of TMED1 was positively correlated with other TMED family members (TMED2, TMED4, TMED9, and TMED10) in CRC, and the protein-protein interaction network suggested its potential impact on immune regulation. Furthermore, TMED1 expression was positively associated with the infiltration levels of regulatory T cells (Tregs), cancer-associated fibroblasts (CAFs), and endothelial cells and negatively correlated with the infiltration levels of CD4+ T cells, CD8+ T cells, and B cells. At last, the CTRP and GDSC datasets on the GSCA platform were used to analyze the relationship between TMED1 expression and drug sensitivity (IC50). The result found that the elevation of TMED1 was positively correlated with IC50 and implied it could increase the drug resistance of cancer cells. This research revealed that TMED1 is a novel prognostic biomarker in CRC and provided a valuable strategy for analyzing potential therapeutic targets of malignant tumors.

Oncolytic Peptide-Nanoplatform Drives Oncoimmune Response and Reverses Adenosine-Induced Immunosuppressive Tumor Microenvironment.

The application of oncolytic peptides has become a powerful approach to induce complete and long-lasting remission in multiple types of carcinomas, as affirmed by the appearance of tumor-associated antigens and adenosine triphosphate (ATP) in large quantities, which jumpstarts the cancer-immunity cycle. However, the ATP breakdown product adenosine is a significant contributor to forming the immunosuppressive tumor microenvironment, which substantially weakens peptide-driven oncolytic immunotherapy. In this study, a lipid-coated micelle (CA@TLM) loaded with a stapled oncolytic peptide (PalAno) and an adenosine 2A receptor (A2AR) inhibitor (CPI-444) is devised to enact tumor-targeted oncolytic immunotherapy and to overcome adenosine-mediated immune suppression simultaneously. The CA@TLM micelle accumulates in tumors with high efficiency, and the acidic lysosomal environment prompts the rapid release of PalAno and CPI-444. Subsequently, PalAno induces swift membrane lysis of tumor cells and the release of antigenic materials. Meanwhile, CPI-444 blocks activation of the immunosuppressive adenosine-A2AR signaling pathway. This combined approach exhibit pronounced synergy at stalling tumor growth and metastasis in animal models for triple-negative breast cancer (TNBC) and melanoma, providing a novel strategy for enhanced oncolytic immunotherapy. This article is protected by copyright. All rights reserved.

Impacts of Aspergillus oryzae 3.042 on the flavor formation pathway in Cantonese soy sauce koji.

To investigate the mechanism of flavor formation during the traditional preparation Cantonese soy sauce koji (TP), the changes of microorganisms, physicochemical properties, and flavor compounds in TP were comprehensively and dynamically monitored by absolute quantitative methods. Results demonstrated that inoculating Aspergillus oryzae 3.042 in TP was crucial role in enhancing enzyme activity properties. Absolute quantification of flavor combined with multivariate statistical analysis yielded 5 organic acids, 15 amino acids, and 2 volatiles as significantly different flavors of TP. Amplicon sequencing and RT-qPCR revealed that the dominant genera were Staphylococcus, Weissella, Enterobacter, Lactic streptococci, Lactobacillus, and Aspergillus, which exhibited a increasing trend in TP. Correlation analysis exhibited that Staphylococcus and Aspergillus were the pivotal genera contributing to the enzyme activities and flavor of TP. The flavor formation network involved lipid and protein degradation, carbohydrate metabolism and other pathways. Simultaneously, TP can appropriately increase the fermentation time to improve product quality.

Progress in RAS-targeted therapeutic strategies: From small molecule inhibitors to proteolysis targeting chimeras.

As a widely considerable target in chemical biology and pharmacological research, rat sarcoma (RAS) gene mutations play a critical driving factor in several fatal cancers. Despite the great progress of RAS subtype-specific inhibitors, rapid acquired drug resistance could limit their further clinical applications. Proteolysis targeting chimera (PROTAC) has emerged as a powerful tool to handle "undruggable" targets and exhibited significant therapeutic benefit for the combat of drug resistance. Owing to unique molecular mechanism and binding kinetics, PROTAC is expected to become a feasible strategy to break the bottleneck of classical RAS inhibitors. This review aims to discuss the current advances of RAS inhibitors and especially focus on PROTAC strategy targeting RAS mutations and their downstream effectors for relevant cancer treatment.