Germline mutations in the tumor suppressor TP53 lead to cancer predisposition, as seen in Li-Fraumeni syndrome (LFS). Currently, no strategies exist to delay or prevent cancer development in this population. Our work is based on the hypothesis that modulating wild-type p53 levels could serve as a prophylactic approach to mitigate cancer risk. By introducing a third copy of Trp53, either constitutively or in an inducible manner in adulthood, we demonstrate that tumor development is delayed, and mice live longer without observable side effects in both the Eu-myc lymphoma and LFS models. Mechanistically, Trp53 loss of heterozygosity is reduced in the LFS model, accompanied by an enhanced p53 transcriptional response. Our findings therefore provide genetic evidence supporting this approach, which could be leveraged to identify compounds that modulate p53 levels and benefit LFS carriers and other cancer-prone populations with reduced p53 activity.

Gilteritinib, a multi-target kinase inhibitor, is currently used as standard therapy for acute myeloid leukemia. However, approximately half of the patients encounter liver-related adverse effects during the treatment with gilteritinib, which limiting its clinical applications. The underlying mechanisms of gilteritinib-induced hepatotoxicity and the development of strategies to prevent this toxicity are not well-reported. In our study, we utilized JC-1 dye, and MitoSOX to demonstrate that gilteritinib treatment leads to hepatocytes undergoing p53-mediated mitochondrial apoptosis. Furthermore, qRT-PCR analysis revealed that DNA damage-inducible transcript 4 (DDIT4), a downstream target of p53, was upregulated following gilteritinib administration and was identified as a key factor in gilteritinib-induced hepatotoxicity. After drug screening and western blot analysis, borneol, a bicyclic monoterpenoid, was found to decrease the protein level of DDIT4. This is the first compound found to downregulate DDIT4 levels and ameliorate hepatic injury caused by gilteritinib. Our findings suggest that high levels of DDIT4 are the primary driver behind gilteritinib-induced liver injury, and that borneol could potentially be a clinically safe and feasible therapeutic strategy by inhibiting DDIT4 levels.

Undruggable targets are those of therapeutical significance but challenging for conventional drug design approaches. Such targets often exhibit unique features, including highly dynamic structures, a lack of well-defined ligand-binding pockets, the presence of highly conserved active sites, and functional modulation by protein-protein interactions. Recent advances in computational simulations and artificial intelligence have revolutionized the drug design landscape, giving rise to innovative strategies for overcoming these obstacles. In this review, we highlight the latest progress in computational approaches for drug design against undruggable targets, present several successful case studies, and discuss remaining challenges and future directions. Special emphasis is placed on four primary target categories: intrinsically disordered proteins, protein allosteric regulation, protein-protein interactions, and protein degradation, along with discussion of emerging target types. We also examine how AI-driven methodologies have transformed the field, from applications in protein-ligand complex structure prediction and virtual screening to de novo ligand generation for undruggable targets. Integration of computational methods with experimental techniques is expected to bring further breakthroughs to overcome the hurdles of undruggable targets. As the field continues to evolve, these advancements hold great promise to expand the druggable space, offering new therapeutic opportunities for previously untreatable diseases.

Globally, breast cancer is the most common malignancy among women and thyroid cancer is also one of the common cancer types among women. Patients with breast cancer exhibit a higher incidence of thyroid cancer than that noted in the general population. The exact mechanism of multiple tumors remains elusive. In the present study, the case of a patient with multiple tumors harboring gene mutation is reported. Specifically, a patient with lymphoepithelioma-like carcinoma of the breast (LELC-B) and thyroid cancer is described. It was hypothesized that the short interval between the onset of these two types of malignant tumor may be related to the TP53 gene mutation status of the patient. To date, a specific relationship between gene mutations and multiple tumors is yet to be determined. Therefore, additional studies are required to address this topic.

Chimeric antigen receptor (CAR) T cell immunotherapy represents a breakthrough in the treatment of hematological malignancies, but poor specificity has limited its applicability to solid tumors. By contrast, natural T cells harboring T cell receptors (TCRs) can discriminate between neoantigen-expressing cancer cells and self-antigen-expressing healthy tissues but have limited potency against tumors. We used a high-throughput platform to systematically evaluate the impact of co-expressing a TCR and CAR on the same CAR T cell. While strong TCR-antigen interactions enhanced CAR activation, weak TCR-antigen interactions actively antagonized their activation. Mathematical modeling captured this TCR-CAR crosstalk in CAR T cells, allowing us to engineer dual TCR/CAR T cells targeting neoantigens (HHATL8F/p53R175H) and human epithelial growth factor receptor 2 (HER2) ligands, respectively. These T cells exhibited superior anti-cancer activity and minimal toxicity against healthy tissue compared with conventional CAR T cells in a humanized solid tumor mouse model. Harnessing pre-existing inhibitory crosstalk between receptors, therefore, paves the way for the design of more precise cancer immunotherapies.

Tumor suppressor genes are frequently targeted by mutations introducing premature termination codons (PTC) in the protein coding sequence, both in sporadic cancers and in the germline of patients with cancer predisposition syndromes. These mutations have a high pathogenic impact since they generate C-terminal truncated proteins with altered stability and function. In addition, PTC mutations trigger transcript degradation by nonsense-mediated mRNA decay. Suppression of PTC by translational readthrough restores protein biosynthesis and stabilizes the PTC-targeted mRNA, making a suitable therapeutic approach the reconstitution of active full-length tumor suppressor proteins by pharmacologically-induced translational readthrough. Here, we review the recent advances in small molecule pharmacological induction of translational readthrough of disease-associated PTC from tumor suppressor genes, and discuss the therapeutic potential of translational readthrough in specific groups of patients with hereditary syndromic cancers.

Dysregulated protein degradation via the ubiquitin-proteasomal pathway can induce numerous disease phenotypes, including cancer, neurodegeneration, and diabetes. While small molecule-based targeted protein degradation (TPD) and targeted protein stabilization (TPS) platforms can address this dysregulation, they rely on structured and stable binding pockets, which do not exist to classically "undruggable" targets. Here, we expand the TPS target space by engineering "deubiquibodies" (duAbs) via fusion of computationally-designed peptide binders to the catalytic domain of the potent OTUB1 deubiquitinase. In human cells, duAbs effectively stabilize exogenous and endogenous proteins in a DUB-dependent manner. Using protein language models to generate target-binding peptides, we engineer duAbs to conformationally diverse target proteins, including key tumor suppressor proteins p53 and WEE1, and heavily-disordered fusion oncoproteins, such as PAX3::FOXO1. We further encapsulate p53-targeting duAbs as mRNA in lipid nanoparticles and demonstrate effective intracellular delivery, p53 stabilization, and apoptosis activation, motivating further in vivo translation.

Developing proteolysis-targeting chimeras (PROTACs) is well recognized through target protein degradation (TPD) toward promising therapeutics. While a variety of diseases are driven by aberrant ubiquitination and degradation of critical proteins with protective functions, target protein stabilization (TPS) rather than TPD is emerging as a unique therapeutic modality. Deubiquitinase-targeting chimeras (DUBTACs), a class of heterobifunctional protein stabilizers consisting of deubiquitinase (DUB) and protein-of-interest (POI) targeting ligands conjugated with a linker, can rescue such proteins from aberrant elimination. DUBTACs stabilize the levels of POIs in a DUB-dependent manner, removing ubiquitin from polyubiquitylated and degraded proteins. DUBTACs can induce a new interaction between POI and DUB by forming a POI-DUBTAC-DUB ternary complex. Herein, therapeutic benefits of TPS approaches for human diseases are introduced, and recent advances in developing DUBTACs are summarized. Relevant challenges, opportunities, and future perspectives are also discussed.

This study aims to characterize PI3K and TP53 pathway alterations in Hispanic/Latino patients with early-onset colorectal cancer (CRC), focusing on potential differences compared to non-Hispanic White patients. Understanding these differences may shed light on the molecular basis of CRC health disparities.

Using cBioPortal, we conducted a bioinformatics analysis to evaluate CRC mutations within the PI3K and TP53 pathways. CRC patients were stratified by age and ethnicity: (1) early-onset (< 50 years) versus late-onset (≥ 50 years) and (2) early-onset in Hispanic/Latino patients compared to early-onset in non-Hispanic White patients. Mutation frequencies were assessed using descriptive statistics, with chi-squared tests comparing proportions between early-onset Hispanic/Latino and non-Hispanic White groups. Kaplan-Meier survival curves were generated to assess overall survival for early-onset Hispanic/Latino patients, stratified by the presence or absence of PI3K and TP53 pathway alterations.

Significant differences were noted when comparing early-onset CRC in Hispanic/Latino patients to early-onset CRC in non-Hispanic White patients. PI3K (47.1% vs. 35.2%, p = 9.39e-3) and TP53 (89.1% vs. 81.7%, p = 0.04) pathway alterations were more prevalent in early-onset CRC among Hispanic/Latino patients, with AKT1 (5.1% vs. 1.8%, p = 0.03), INPP4B (4.3% vs. 1.4%, p = 0.04), and TSC1 (7.2% vs. 3.1% p = 0.03) gene alterations also significantly higher in this group. Significant differences were observed in TP53 mutations between colon adenocarcinomas (90% vs. 79.1%, p = 0.03), with higher prevalence in Hispanic/Latino patients when stratified by tumor site. No significant differences were observed between early-onset and late-onset CRC patients within the Hispanic/Latino cohort.

These findings highlight the distinct role of PI3K and TP53 pathway disruptions in early-onset CRC among Hispanic/Latino patients, suggesting that pathway-specific mechanisms may drive cancer health disparities. Insights from this study could inform the potential development of precision medicine approaches and targeted therapies aimed at addressing these disparities.

Cholangiocarcinoma (CCA) is a serious public health issue due to its insidious onset and dismal prognosis. The past few years have witnessed and highlighted the development of understanding and management of CCA. The combination of gemcitabine and cisplatin (GP) chemotherapy regimen with immunotherapy using immune checkpoint inhibitors has been considered the new standard first-line treatment alternative for advanced CCA. Notably, the proportion of patients with advanced CCA with targetable genetic mutations is approximately 40 %, and these patients may be considered for molecularly targeted therapy in the second-line treatment. In this review, we highlight the advances and progress in targeted therapies for advanced CCA, with special attention to data from Asian populations, including Chinese. In addition, we present in detail the phosphatase tension homolog (PTEN), a novel biomarker for both of first-line chemotherapy and second-line targeted therapy in advanced CCA, and its ability to forecast prognosis in patients with CCA. The mechanisms of rapid resistance to targeted agents warrant further investigation and address in light of the development of new targeted therapies. Precision medicine is gradually playing an increasing role in achieving optimal therapeutic outcomes.

The tumor microenvironment is highly heterogeneous and consists of neoplastic cells and diverse stromal components, including fibroblasts, endothelial cells, pericytes, immune cells, local and bone marrow-derived stromal stem and progenitor cells, and the surrounding extracellular matrix. Although the significance of p16 and p53 has been reported in various tumor types, their involvement in the stromal cells of oral squamous cell carcinoma (OSCC) remains unclear. We performed immunohistochemical analyses of p16 and p53 expression in OSCC samples, Of the 116 samples, 74 showed p16-positive stromal cells, and 33 showed p53-positive stromal cells. Both p16 and p53 positivity were associated with an increased histological grade, lymphovascular invasion, an immature stromal pattern with abundant amorphous extracellular matrix material, infiltrative invasion patterns (Yamamoto Kohama classification-4C and 4D), and poor prognosis. Multivariate analyses identified p16 and p53 positivity in the stroma as independent prognostic factors for overall survival (P = 0.032 and P = 0.020, respectively); moreover, stromal p16 positivity correlated with stromal p53 positivity. These findings indicated that p16 and p53 stroma positivity may regulate OSCC tumor aggressiveness.

This study explores evolved Hyaluronidase, Lipase, and Elastase's identification, characterization, and therapeutic potential to enhance tissue regeneration and drug delivery systems in otolaryngology. Hyaluronidase variant H5 exhibited a turnover number (k_cat) of 1500 min-1, a 200 % increase over wild-type (500 min-1), demonstrating superior hyaluronic acid degradation. Similarly, lipase variant L2 reached 1200 min-1 (400 min-1 wild-type), and elastase variant E3 showed a turnover of 2200 min-1 (1000 min-1 wild-type). Kinetic analyses revealed improved Km and Vmax values across variants, with Hyaluronidase Variant H5 achieving Km = 1.5 μM and Vmax = 3000 μM/min. Molecular Dynamics (MD) simulations indicated structural stability (average RMSD ~1.5 Å for H5) and strong hydrogen bonding (180 bonds), enhancing catalytic efficiency. In vitro assays demonstrated a 40 % enhancement in tissue regeneration and increased epithelial cell proliferation (100 % for Hyaluronidase Variant H5 vs. 60 % wild-type). In vivo studies in rabbits revealed a 30 % reduction in recovery time post-sinus surgery and a 50 % reduction in scar tissue formation. These findings underscore the potential of evolved enzymes in advancing drug delivery (DD) and tissue repair (TR), with implications for broader applications in wound healing and inflammatory diseases.

Cancer is complex because of the critical imbalance in genetic regulation as characterized by both the overexpression of oncogenes (OGs), mainly through mutations, amplifications, and translocations, and the inactivation of tumor-suppressor genes (TSGs), which entail the preservation of genomic integrity by inducing apoptosis to counter the malignant growth. Reviewing the intricate molecular interplay between OGs and TSGs draws attention to their cell cycle, apoptosis, and cancer metabolism regulation. In the present review, we discuss seminal discoveries, such as Knudson's two-hit hypothesis, which framed the field's understanding of cancer genetics, leading to the next breakthroughs with next-generation sequencing and epigenetic profiling, revealing novel insights into OG and TSG dysregulation with opportunities for targeted therapy. The key pathways, such as MAPK/ERK, PI3K/AKT/mTOR, and Wnt/β-catenin, are presented in the context of tumor progression. Importantly, we further highlighted the advances in therapeutic strategies, including inhibitors of KRAS and MYC and restoration of TSG function, despite which mechanisms of resistance and tumor heterogeneity pose daunting challenges. A high-level understanding of interactions between OG-TSGs forms the basis for effective, personalized cancer treatment-something to strive for in better clinical outcomes. This synthesis should integrate foundational biology with translation and, in this case, contribute to the ongoing effort against cancer.

Tumor suppressor p53 is the most frequently mutated protein in cancer, possessing untapped immune-modulating capabilities in anticancer treatment. Here, we investigate the efficacy and underlying mechanisms of pharmacological reactivation of mutant p53 in treating spontaneous tumors in mice. In the p53 R279W (equivalent to the human hotspot R282W) mouse model developing spontaneous tumors, arsenic trioxide (ATO) treatment through drinking water significantly prolongs the survival of mice, dependent on p53-R279W reactivation. Transient regressions of spontaneous T-lymphomas are observed in 70% of the ATO-treated mice, accompanied by interferon (IFN) response. In allograft models, the tumor-suppressive effect of reactivated p53-R279W is detectably reduced in both immunodeficient Rag1-/- and CD8+ T cell-depleted mice. ATO also activates the IFN pathway in human cancer cells harboring various p53 mutations, as well as in primary samples derived from the p53-mutant patient treated with ATO. Together, p53 could serve as an alternative therapeutic target for the development of immunotherapies.

Colorectal cancer (CRC) is the most prevalent cancer globally, and its traditional treatment modalities commonly encompass radiation therapy, chemotherapy, surgery and the administration of cytotoxic drugs. Currently, novel chemotherapy drugs that combine traditional Chinese medicine (TCM) with herbal extracts exhibit superior comprehensive benefits. Herein, we delved into an article authored by Wang et al, focusing specifically on the pharmacological effects of "Herba Patriniae and Coix seed (HC)" and their targeted mechanisms in combating CRC. From the perspective of TCM philosophy, damp-heat stagnation and toxicity are the cardinal pathogenic factors underlying CRC. HC, renowned for their abilities to antipyretic and enhance diuresis, have demonstrated promising efficacy in preliminary studies for the treatment of CRC. These findings offer potential insights in favor of fostering anti-cancer medications.

Tumor suppressor genes (TSGs) are thought to suppress tumor development primarily via cancer cell-autonomous mechanisms. However, the tumor microenvironment (TME) also significantly influences tumorigenesis. In this context, a role for TSGs in the various cell types of the TME in regulating tumor growth is emerging. Indeed, expression analyses of TSGs in clinical samples, along with data from mouse models in which TSGs were deleted selectively in the TME, indicate a functional role for them in tumor development. In this Perspective, using TP53 and PTEN as examples, we posit that TSGs play a significant role in cells of the TME in regulating tumor development, and postulate both a 'pro-active' and 'reactive' model for their contribution to tumor growth, dependent on the temporal sequence of initiating events. Finally, we discuss the need to consider a 2-in-1 cancer-treatment strategy to improve the efficacy of clearance of cancer cells and the cancer-promoting TME.

Leukemia is a type of blood cancer characterized by the uncontrolled growth of abnormal cells in the bone marrow, which replace normal blood cells and disrupt normal blood cell function. Timely and personalized interventions are crucial for disease management and improving survival rates. However, many patients experience relapse following conventional chemotherapy, and increasing treatment intensity often fails to improve outcomes due to mutated gene-induced drug resistance in leukemia cells. This article analyzes the association of gene mutations and drug resistance in leukemia. It explores genetic abnormalities in leukemia, highlighting recently identified mutations affecting signaling pathways, cell apoptosis, epigenetic regulation, histone modification, and splicing mechanisms. Additionally, the article discusses therapeutic strategies such as molecular targeting of gene mutations, alternative pathway targeting, and immunotherapy in leukemia. These approaches aim to combat specific drug-resistant mutations, providing potential avenues to mitigate leukemia relapse. Future research with these strategies holds promise for advancing leukemia treatment and addressing the challenges of drug-resistant mutations to improve patient outcomes.

Colorectal cancer is one of the most prevalent malignancies worldwide, with a tendency of increasing incidence in developed countries, which poses a significant threat to the patients' physical and mental health.

The process of gene transcription affects the important physiological functions of cells, so the normal expression of transcription factors is an important prerequisite for maintaining cellular homeostasis. Changes in the level of zinc finger proteins, the most prevalent transcription factor, may play an important trigger for the development of colorectal cancer. Different zinc finger proteins play different roles in terms of promoting or inhibiting cancer development.

This paper briefly reviews the classification, functional characteristics, and expression changes of zinc finger proteins in colorectal cancer, it focuses on how they regulate gene transcription, influence on common signaling pathways, and their potential for translational studies and clinical applications. The objective is to stimulate new ideas for their study of colorectal cancer while also providing foundational information to guide drug development and treatment strategies for colorectal cancer patients in clinical settings.

Cancers represent a significant global health burden, affecting millions of individuals each year [...].

Tumor progression is suppressed by inherent cellular mechanisms such as apoptosis. The p53 tumor suppressor gene is the most commonly mutated gene in human cancer and plays a pivotal role in tumor suppression. RPRM is a target gene of p53 known to be involved in tumor suppression, but its molecular function has remained elusive. Here, we report that Reprimo (the protein product of RPRM) is secreted and extrinsically induces apoptosis in recipient cells. We identified FAT1, FAT4, CELSR1, CELSR2, and CELSR3, members of the protocadherin family, as receptors for Reprimo. Subsequent analyses revealed that Reprimo acts upstream of the Hippo-YAP/TAZ-p73 axis and induces apoptosis by transactivating various proapoptotic genes. In vivo analyses further support the tumor-suppressive effects of secreted Reprimo. These findings identify the p53-Reprimo-Hippo-YAP/TAZ-p73 axis as an extrinsic apoptosis pathway that plays a crucial role in tumor suppression. Our finding of the innate tumor eliminator Reprimo and the downstream pathway offers a promising avenue for the pharmacological treatment of cancer.

Nasopharyngeal carcinoma (NPC) is a malignant tumor originated from the nasopharynx epithelial cells and has been linked with Epstein-Barr virus (EBV) infection, dietary habits, environmental and genetic factors. It is a common malignancy in Southeast Asia, especially with gender preference among men. Due to its non-specific symptoms, NPC is often diagnosed at a late stage. Thus, the molecular diagnosis of NPC plays a crucial role in early detection, treatment selection, disease monitoring, and prognosis prediction. This review aims to provide a summary of the current state and the latest emerging molecular diagnostic techniques for NPC, including EBV-related biomarkers, gene mutations, liquid biopsy, and DNA methylation. Challenges and potential future directions of NPC molecular diagnosis will be discussed.

Inactivation of p53 by mutations commonly occurs in human cancer. The mutated p53 proteins may escape proteolytic degradation and exhibit high expression in tumors and acquire gain-of-function activity that promotes tumor progression and chemo-resistance. Therefore, selectively targeting of the gain-of-function p53 mutants may serve as a promising therapeutic strategy for cancer prevention and treatment. In this study, we identified cabozantinib, a multikinase inhibitor currently used in the clinical treatment of several types of cancer, as a selective inducer of proteasomal degradation of the p53-Y220C mutant. We demonstrate that cabozantinib disrupts the interaction between p53Y220C and USP7, a deubiquitylating enzyme, resulting in the dissociation of p53Y220C protein from its binding with USP7 and subsequent ubiquitination and degradation mediated by CHIP (the carboxyl terminal of Hsp70-interacting protein). We also show that cabozantinib displays preferential cytotoxicity to p53Y220C-harboring cancer cells both in vitro and in vivo. This study demonstrates a novel, p53-Y220C mutant-targeted anticancer action and mechanism for cabozantinib and provides the rationale for use of this drug in the treatment of cancers that carry the p53-Y220C mutation.

The present study aimed to develop a nomogram model for predicting overall survival (OS) in esophageal squamous cell carcinoma (ESCC) patients.

A total of 205 patients with ESCC were enrolled and randomly divided into a training cohort (n = 153) and a test cohort (n = 52) at a ratio of 7:3. Multivariate Cox regression was used to construct the radiomics model based on CT data. The mutation signature was constructed based on whole genome sequencing data and found to be significantly associated with the prognosis of patients with ESCC. A nomogram model combining the Rad-score and mutation signature was constructed. An integrated nomogram model combining the Rad-score, mutation signature, and clinical factors was constructed.

A total of 8 CT features were selected for multivariate Cox regression analysis to determine whether the Rad-score was significantly correlated with OS. The area under the curve (AUC) of the radiomics model was 0.834 (95% CI, 0.767-0.900) for the training cohort and 0.733 (95% CI, 0.574-0.892) for the test cohort. The Rad-score, S3, and S6 were used to construct an integrated RM nomogram. The predictive performance of the RM nomogram model was better than that of the radiomics model, with an AUC of 0. 830 (95% CI, 0.761-0.899) in the training cohort and 0.793 (95% CI, 0.653-0.934) in the test cohort. The Rad-score, TNM stage, lymph node metastasis status, S3, and S6 were used to construct an integrated RMC nomogram. The predictive performance of the RMC nomogram model was better than that of the radiomics model and RM nomogram model, with an AUC of 0. 862 (95% CI, 0.795-0.928) in the training cohort and 0. 837 (95% CI, 0.705-0.969) in the test cohort.

An integrated nomogram model combining the Rad-score, mutation signature, and clinical factors can better predict the prognosis of patients with ESCC.

The p53 protein is regarded as the "Guardian of the Genome," but its mutation is tumor progression and present in more than half of malignant tumors. The pro-metastatic property of mutant p53 makes a strong argument for targeting mutant p53 with new therapeutic strategies. However, mutant p53 was considered as a challenging target for drug discovery due to the lack of small molecular binding pockets. Among them, mutant p53 Y220C creates a narrow crevice since the side chains dynamics on protein surface, which is suitable for designing small molecules to occupy the cavity and recovery the tumor suppressing function. Here, we describe the mechanism of p53 related signal pathway and how p53 Y220C regulate the tumorigenesis. We review the two types of p53 Y220C modulators including restoring the conformation of mutant p53 Y220C protein to wild-type p53 protein and recruiting histone acetyltransferase p300/CBP to acetylate p53 Y220C thus enables p53 Y220C dependent upregulation of apoptotic genes and downregulation of DNA damage response pathways. We also report clinical advances and challenges of these molecules in p53 Y220C medicated tumor therapy.

About 50% of all cancers carry a mutation in p53 that impairs its tumor suppressor function. The p53 missense mutation p53R175H (p53R172H in mice) is a hotspot mutation in various cancer types. Therefore, monoclonal antibodies selectively targeting clinically relevant mutations like p53R175H could prove immensely value. We aimed to evaluate the in vitro and in vivo binding properties of two novel anti-p53R175H monoclonal antibodies and to assess their performance as agents for molecular imaging. In vitro, 125I-4H5 and 125I-7B9 demonstrated long shelf life and antigen-specific binding. Our in vivo study design allowed head-to-head comparison of the antibodies in a double tumor model using repeated SPECT/CT imaging, followed by biodistribution and autoradiography. Both tracers performed similarly, with marginally faster blood clearance for 125I-7B9. Repeated molecular imaging demonstrated suitable imaging characteristics for both antibodies, with the best contrast images occurring at 48 h post-injection. Significantly higher uptake was detected in the mut-p53-expressing tumors, confirmed by ex vivo autoradiography. We conclude that molecular imaging with an anti-p53R175H tracer could be a promising approach for cancer diagnostics and could be further applied for patient stratification and treatment response monitoring of mutant p53-targeted therapeutics.

The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized cancer therapy.

The discovery of effective breast cancer therapy is both urgent and daunting, beset by a myriad of challenges that range from the disease's inherent heterogeneity to its complex molecular underpinnings. Drug resistance, the intricacies of the tumor microenvironment, and patient-specific variables further complicate this landscape. The stakes are even higher when dealing with subtypes like triple-negative breast cancer, which eludes targeted hormonal therapies due to its lack of estrogen, progesterone, and HER2 receptors. Strategies to overcome such challenges include combinations of drugs and identifying new drug targets. Developing new drugs based on such targets could be a better solution than relying on costly immunotherapy or combinational therapies. In this review, we have endeavored to comprehensively examine the proven therapeutic drug targets associated with breast cancer and elucidate their respective molecular mechanisms and current clinical status. This study aims to facilitate researchers in conducting a comparative analysis of different targets to select single and multi-targeted drug discovery approaches for breast cancer.

The impairment of the p53 pathway was once regarded as inadequately druggable due to the specificity of the p53 structure, its flat surface lacking an ideal drug-binding site, and the difficulty in reinstating p53 function. However, renewed interest in p53-based therapies has emerged, with promising approaches targeting p53 and ongoing clinical trials investigating p53-based treatments across various cancers. Despite significant progress in p53-targeted therapies, challenges persist in identifying effective therapeutic targets within the p53 pathway. In this study, we implemented a molecular screening system to effectively discover p53 activator. As a result, illudin S was identified as a potential inhibitor of the p53-Mdm2 interaction. This compound is particularly intriguing due to its well-documented anti-cancer effects, despite the ambiguity surrounding its precise mechanism of action. Illudin S demonstrated a direct binding affinity to the Mdm2 binding site of p53 through hydrogen bonding, which enhanced the stability and transcriptional activity of p53. The inhibition of the p53-Mdm2 interaction by illudin S led to increased p53 expression. Moreover, this inhibition effectively induced apoptosis and cell cycle arrest in CT26 colorectal cancer cells. Administration of illudin S in a colorectal cancer mouse model resulted in prolonged survival and significant tumor growth inhibition. These findings elucidate the mechanism underlying the anti-cancer effects of illudin S, specifically through its targeting of the p53-Mdm2 interaction in colorectal cancer. Consequently, illudin S emerges as a promising candidate for the development of p53-targeted cancer therapies.

The recurrence of glioma after treatment has remained an intractable problem for many years. Recently, numerous studies have explored the pivotal role of the mouse double minute 2 (MDM2)/p53 pathway in cancer treatment. Lysine phosphate phosphohistidine inorganic pyrophosphate phosphatase (LHPP), a newly discovered tumor suppressor, has been confirmed in numerous studies on tumors, but its role in glioma remains poorly understood. Expression matrices in The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases were analyzed using gene set enrichment analysis (GSEA), revealing significant alterations in the p53 pathway among glioma patients with high LHPP expression. The overexpression of LHPP in glioma cells resulted in a reduction in cell proliferation, migration, and invasive ability, as well as an increase in apoptosis and alterations to the cell cycle. The present study has identified a novel inhibitory mechanism of LHPP against glioma, both in vivo and in vitro. The results demonstrate that LHPP exerts anti-glioma effects via the MDM2/p53 pathway. These findings may offer a new perspective for the treatment of glioma in the clinic.

The p53 tumor suppressor is one of the most mutated genes responsible for tumorigenesis in most human cancers. Out of 29,891 genomic mutations reported in the TP53 Database (https://tp53.isb-cgc.org/), 1,297 are identified as unique missense somatic mutations excluding frameshift, intronic, deletion, nonsense, silent, splice, and other unknown mutations. We have comprehensively analyzed all these 1,297 unique missense mutations and created a phenotypical map based on the distribution of mutations in each domain, the functional state of the protein, and their occurrence in different types of tissues and organs. Our mutation map shows that almost 118 unique missense mutations are reported in the transactivation and proline-rich domains, 1,065 in the central DNA-binding domains, and 113 in the oligomerization and regulatory domains. Based on the phenotype, these mutations are subdivided into 46 super trans, 491 functional, 315 partially functional, and 415 non-functional mutations. The prevalence of these mutations was checked in 71 different types of tissues and found that the mutant R248Q is reported in 51 types of tissues followed by R175H and R273H in 46 types. We correlated the potential impact of mutation in target gene transcription and regulation with nucleosomal DNA and RNA-Pol II complexes. We have discussed the impact of mutation at post-translational modification sites in the structure and function of p53 highlighting the potential therapeutic drug targets with tremendous clinical applications.

The TP53 mutation is one of the most common gene mutations in non-small cell lung cancer (NSCLC) and plays a significant role in the occurrence, development, and prognosis of both lung adenocarcinoma (LUAD) and lung squamous cell carcinoma (LUSC). Recent studies have also suggested the predictive value of TP53 mutations in the response to immunotherapy for NSCLC. It is known that intratumoral microbiota, tumor immune microenvironment (TIME) and histology are associated with the roles of TP53 mutation in NSCLC. However, the intrinsic associations among these three factors and their underlying interaction with TP53 mutation are not well understood. Additionally, the potential of predicting TP53 mutations using deep learning methods has not yet been fully evaluated. In this paper, we comprehensively evaluated the tissue microbiome, host gene expression characteristics, and histopathological slides of 992 NSCLC patients obtained from the cancer genome atlas (TCGA) and validated the findings using multi-omics data of 332 NSCLC patients from the Clinical Proteomic Tumor Analysis Consortium (CPTAC). Compared to LUSC, LUAD exhibited more substantial differences between patients with and without TP53 mutation in all three aspects. In LUAD, our results imply underlying links between the tissue microbiome and immune cell components in the TIME, and show that the abundance of immune cells is reflected in histology slides. Furthermore, we propose a novel multimodal deep learning model that focuses on histopathology images, which achieves an area under the curve (AUC) of 0.84 in LUAD. In summary, TP53 mutation of LUAD resulted more significant changes in intratumoral microbiota, TIME and histology than that of LUSC. And histopathology images can be used to predict TP53 mutation in LUAD with reasonable accuracy.