Target For Cancer Treatment Research Articles

RRM1 promotes homologous recombination and radio/chemo-sensitivity via enhancing USP11 and E2F1-mediated RAD51AP1 transcription

Ribonucleotide reductase M1 (RRM1), the catalytic subunit of ribonucleotide reductase, plays a pivotal role in converting ribonucleotides (NTP) into deoxyribonucleotides (dNTP), essential for DNA replication and repair. Elevated RRM1 expression is associated with various human cancers, correlating with poorer prognosis and reduced overall survival rates. Our previous study found that RRM1 will enter the nucleus to promote DNA damage repair. However, the underlying mechanism remains elusive. Here, we unveil a novel role of RRM1 in promoting homologous recombination (HR) by upregulating the expression of RAD51AP1, a critical HR factor, in an E2F1-dependent manner. We demonstrate that RRM1 interacts with USP11 in the cytoplasm, and the recruitment of RRM1 to LaminB1 induced by ionizing radiation (IR) facilitates the binding of USP11 to the nuclear pore complex (NPC), promoting USP11 entry into the nucleus. Upon nuclear translocation, USP11 binds to E2F1 and inhibits the ubiquitin-mediated degradation of E2F1, thereby enhancing the transcriptional expression of RAD51AP1. Moreover, a specific RRM1 mutant lacking amino acids 731–793, crucial for its interaction with USP11 and recruitment to LaminB1, exhibits a dominant-negative effect on RAD51AP1 expression and HR. Truncations of RRM1 fail to inhibit the ubiquitin-mediated degradation of E2F1 and cannot promote the E2F1-mediated transactivation of RAD51AP1. Lastly, the full length of RRM1, not truncations, enhances tumor cells’ sensitivity to IR, underscoring its importance in radiotherapy resistance. Collectively, our results suggest a novel function of RRM1 in promoting HR-mediated DSB repair through positive regulation of RAD51AP1 transcription by direct interaction with USP11 and promoting subsequent USP11-mediated deubiquitination of E2F1. Our findings elucidate a previously unknown mechanism whereby RRM1 promotes HR-mediated DNA repair, presenting a potential therapeutic target for cancer treatment.

Challenges in Implementing Comprehensive Precision Medicine Screening for Ovarian Cancer

Precision medicine has revolutionised targeted cancer treatments; however, its implementation in ovarian cancer remains challenging. Diverse tumour biology and extensive heterogeneity in ovarian cancer can limit the translatability of genetic profiling and contribute to a lack of biomarkers of treatment response. This review addresses the barriers in precision medicine for ovarian cancer, including obtaining adequate and representative tissue samples for analysis, developing functional and standardised screening methods, and navigating data infrastructure and management. Ethical concerns related to patient consent, data privacy and health equity are also explored. We highlight the socio-economic complexities for precision medicine and propose strategies to overcome these challenges with an emphasis on accessibility and education amongst patients and health professionals and the development of regulatory frameworks to support clinical integration. Interdisciplinary collaboration is essential to drive progress in precision medicine to improve disease management and ovarian cancer patient outcomes.

Histone lactylation as a driver of metabolic reprogramming and immune evasion

Abstract Lactate is the end product of glycolysis, and extensive research has shown that lactate participates in various pathophysiological processes. Along with associated hydrogen ions, lactate typically functions as an immunosuppressive negative factor and plays a crucial role in tumor metabolic reprogramming. The recently discovered lactylation is a novel epigenetic modification that, similar to other epigenetic modifications, modifies histones to alter chromatin spatial configuration, thereby affecting DNA accessibility and regulating gene expression. More importantly, the degree of lactylation is closely related to local lactate concentrations, establishing a link between epigenetics and metabolic reprogramming. During cellular metabolism, lactate accumulation promotes histone lysine lactylation in cancer cells and immune cells such as macrophages and T cells, playing an essential role in tumor immune evasion and resistance to immunotherapy. This paper details the role of lactylation modifications in cancer immune evasion and resistance to immunotherapy, providing novel therapeutic directions and targets for cancer treatment.

Implantable Biomaterials for Cancer Immunotherapies

AbstractCancer immunotherapy has revolutionized cancer treatment by leveraging the immune system to target and eliminate tumor cells. Implantable biomaterials, such as hydrogels, sponges, scaffolds, implantable microdevice platforms, and macrobeads, offer localized and sustained release of immunomodulatory agents, improving the delivery of treatments such as immune checkpoint inhibitors, cancer vaccines, and adoptive cell therapies like CAR‐T cells. This review examines the emerging role of these biomaterials in modulating the tumor microenvironment, enhancing immune cell recruitment, and reducing systemic side effects, positioning them as significant tools for treating solid tumors. Recent advances in material engineering are also discussed, including the integration of bioactive molecules and real‐time therapeutic adjustments based on patient‐specific immune responses, which offer new potential in personalized cancer treatments. However, challenges such as biocompatibility, high production costs, variability in patient response, and the necessity of surgical manipulations remain key obstacles. Nonetheless, ongoing research and technological advancements are steadily addressing these issues, paving the way for more effective and accessible cancer immunotherapies. Overall, this review highlights the promise of implantable biomaterials overcoming the current limitations of cancer immunotherapy and expanding the scope of effective, targeted cancer treatments.

Role of transcription factors in metastasis of breast cancer

Metastasis causes a majority of deaths in breast cancer patients. Metastasis is the spread of cancer to distant sites in the body away from the primary tumor, creating secondary tumors, or metastases. A tumor metastasizes when cancer cells strategically regulate genes that play a role in angiogenesis, epithelial-mesenchymal transition (EMT), migration, invasion, and regulation of the cell cycle to bypass apoptosis and increase proliferation and stemness. Several transcription factors have also been identified to play a role in metastatic breast cancer, as they enable invasion, intravasation, transport, extravasation, and colonization of metastasis through other processes such as angiogenesis and EMT, making them a prime target for cancer treatment. Understanding how transcription factors play a role in breast cancer metastasis will enable the development of targeted therapeutics for breast cancer. This paper reviews the roles of E2Fs, hypoxia-inducible factors (HIFs), EMT master regulators, sex determining region Y (SRY)-related high-mobility group (HMG) box (SOX), E26 transformation-specific (ETS), Yin Yang 1 (YY1), forkhead box M1 (FoxM1), BTB domain and CNC homology 1 (Bach1), sineoculis homeobox homolog (SIX), runt-related transcription factor 2 (RUNX2), myelocytomatosis (MYC), Kruppel-like factors (KLFs), and c-Jun in breast cancer metastasis.

Mutational heterogeneity in large B-cell lymphoma: insights from paired biopsies.

Large B-cell lymphoma (LBCL) exhibits striking clinical and molecular heterogeneity. New approaches have emerged to explore tumor heterogeneity and classify LBCL into biological categories. Consequently, the informational requirements from diagnostic samples to provide the necessary information have increased, but the adequacy of single-site biopsies to provide such information is largely unknown. Here we describe spatial and temporal intra-patient variations in the mutational landscape of paired biopsies. Paired biopsies from 30 patients with LBCL were obtained from spatially distinct sites at the time of primary diagnosis before treatment and/or at a subsequent relapse. The samples were sequenced using a custom designed 59-gene next generation sequencing (NGS) lymphoma panel. Differences in detected mutations of pathogenic or likely pathogenic significance were frequent both when comparing paired diagnostic biopsies, 2/6 (33%), and when comparing paired biopsies at primary diagnosis and relapse, 8/16 (50%). Mutational heterogeneity tended to increase with longer time interval between biopsies. Analysis of paired diagnostic and relapse biopsies revealed that certain clones present at diagnosis disappeared, while new clones emerged at relapse. Notably, TP53 mutations were detected in six out of seven patients in an extranodal location. In two cases, TP53 mutation was only detected in the relapse biopsy. Several of the mutations identified in this study are used or under investigation as targets for cancer treatments. Multi-site biopsies revealed spatial and temporal mutational heterogeneity in patients with LBCL. Our findings indicate that mutational differences between biopsy pairs can occur at all timepoints examined. This underscores the necessity of performing repeat biopsies with each relapse to capture the full spectrum of genetic aberrations.

BIRC5 as a prognostic and diagnostic biomarker in pan-cancer: an integrated analysis of expression, immune subtypes, and functional networks

IntroductionBIRC5 (Survivin) is a crucial anti-apoptotic protein overexpressed in various cancers, promoting tumor growth and treatment resistance. This study investigates its expression across 33 cancer types and explores its diagnostic, prognostic, and immune-related significance.MethodsWe analyzed RNA-seq data from TCGA and protein expression data from the Human Protein Atlas. Expression levels were compared between tumor and normal tissues. Correlations with molecular and immune subtypes were explored using TISIDB. Prognostic significance was evaluated through survival analysis, Cox regression, and ROC curve analysis. The PPI network was constructed using STRING.ResultsBIRC5 was significantly overexpressed in tumor tissues across 33 cancer types, with higher expression levels observed in tumors compared to normal tissues. The protein expression analysis revealed a similar trend. BIRC5 expression was significantly correlated with various molecular and immune subtypes in multiple cancer types. Survival analysis indicated that high BIRC5 expression was associated with poor prognosis across multiple cancers, including lung adenocarcinoma (LUAD) and kidney renal clear cell carcinoma (KIRC). ROC analysis showed that BIRC5 exhibited strong diagnostic potential, with high AUC values (>0.9) in several cancers. The PPI network analysis identified key interacting proteins involved in the cell cycle and tumor progression, further supporting BIRC5's role in cancer biology. Functional experiments in lung adenocarcinoma (LUAD) revealed that BIRC5 upregulation enhances cell proliferation, migration, and invasion, while its knockdown suppresses these activities.DiscussionBIRC5 is a promising diagnostic and prognostic biomarker in multiple cancers. Its association with immune subtypes suggests a potential role in the tumor immune microenvironment. These findings support BIRC5 as a therapeutic target for cancer treatment.

Engineered Reactive Oxygen Species (ROS)-Responsive Artificial H+/Cl- Ion Channels for Targeted Cancer Treatment.

Reactive oxygen species (ROS)-responsive ion channels regulate the ion flow across the membranes in response to alterations in the cellular redox state, playing a crucial role in cellular adaptation to oxidative stress. Despite their significance, replicating ROS-responsive functionality in artificial ion channels remains elusive. In this study, we introduce a novel class of artificial H+/Cl- ion channels activatable by elevated ROS levels in cancer cells. ROS-induced decaging of the phenylboronate group triggers the rapid release of the channel-forming units, leading to self-assembly of the H-bonded cascades facilitating the synergistic transport of H+ and Cl- ions, with H+/Cl- ion transport selectivity of 7.7. Upon activation, ROS-C-Cl exhibits significant apoptotic activity against human breast cancer cells, achieving an IC50 of 2.8 μM, comparable to that of paclitaxel. Exploiting the intrinsic oxidative microenvironment of cancer cells, along with the enhanced oxidative stress arising from H+/Cl- co-transport, ROS-C-Cl demonstrates exceptional selectivity in targeting cancer cells with a selectivity index of 10.2 over normal breast cells, outperforming that of paclitaxel by 19.4 folds.

Engineered Reactive Oxygen Species (ROS)‐Responsive Artificial H+/Cl− Ion Channels for Targeted Cancer Treatment

Reactive oxygen species (ROS)‐responsive ion channels regulate the ion flow across the membranes in response to alterations in the cellular redox state, playing a crucial role in cellular adaptation to oxidative stress. Despite their significance, replicating ROS‐responsive functionality in artificial ion channels remains elusive. In this study, we introduce a novel class of artificial H+/Cl‐ ion channels activatable by elevated ROS levels in cancer cells. ROS‐induced decaging of the phenylboronate group triggers the rapid release of the channel‐forming units, leading to self‐assembly of the H‐bonded cascades facilitating the synergistic transport of H+ and Cl‐ ions, with H+/Cl‐ ion transport selectivity of 7.7. Upon activation, ROS‐C‐Cl exhibits significant apoptotic activity against human breast cancer cells, achieving an IC50 of 2.8 μM, comparable to that of paclitaxel. Exploiting the intrinsic oxidative microenvironment of cancer cells, along with the enhanced oxidative stress arising from H+/Cl‐ co‐transport, ROS‐C‐Cl demonstrates exceptional selectivity in targeting cancer cells with a selectivity index of 10.2 over normal breast cells, outperforming that of paclitaxel by 19.4 folds.

Discovery of KPT-6566 as STAG1/2 Inhibitor sensitizing PARP and NHEJ Inhibitors to suppress tumor cells growth in vitro

Stromal antigen 1 and 2 (STAG1 and STAG2) are two mutually exclusive components of the cohesin complex that is crucial for centromeric and telomeric cohesion. Beyond its structural role, STAG2 also plays a pivotal role in homologous recombination (HR) repair and has emerged as a promising therapeutic target in cancer treatment. Here, we employed a fluorescence polarization (FP)-based high-throughput screening and identified KPT-6566 as a dual inhibitor of STAG1 and STAG2. Biochemical and biophysical analyses demonstrated that KPT-6566 directly binds to STAG1 and STAG2, disrupting their interactions with SCC1 and double-stranded DNA. A metaphase chromosome spread assay showed that KPT-6566 causes premature chromosome separation and induces chromosome damages in HeLa cells. Furthermore, KPT-6566 also impairs DNA damage repair, leading to the accumulation of double-strand breaks and cell apoptosis. Finally, KPT-6566 can sensitize HeLa and HepG2 cells to PARP inhibitor Olaparib and the NHEJ inhibitor UMI-77, exhibiting a synergistic effect in suppressing cell proliferation. Our findings highlight the potential of STAG1/2 as promising therapeutic targets in cancer treatment, particularly when they are targeted in combination with other DNA damage response inhibitors.

Inhibition of CDGSH iron‑sulfur domain 2 exhibits tumor-suppressing effects on diffuse large B-cell lymphoma (DLBCL) by inducing ferroptosis through the regulation of the NRF2/SLC7A11/GPX4 pathway

CDGSH iron‑sulfur domain 2 (CISD2) is recognized as a ferroptosis-related gene that has potential as a target for cancer treatment. However, it is still uncertain whether targeting CISD2 can modulate ferroptosis in diffuse large B-cell lymphoma (DLBCL) cells and exhibit cancer-suppressing effects. The present study thoroughly investigated the role of CISD2 in DLBCL. CISD2 was found to be overexpressed in DLBCL, and its inhibition resulted in substantial growth inhibition in DLBCL cells. The growth inhibition effect resulting from CISD2 silencing could be reversed by a ferroptosis inhibitor, whereas inhibitors of apoptosis and necrosis did not yield the same reversal. CISD2-silenced DLBCL cells exhibited increased sensitivity to growth inhibition induced by ferroptosis suppressors. The inhibition of CISD2 induced ferroptotic cell death in DLBCL cells, which was supported by the overproduction of lipid peroxides, depletion of glutathione, accumulation of iron, and increased presence of shrunken mitochondria. Further investigation revealed reduced levels of NRF2, GPX4, and SLC7A11 in CISD2-silenced DLBCL cells. The overexpression of NRF2 significantly reduced the occurrence of ferroptotic cell death in DLBCL cells in which CISD2 was silenced. Furthermore, CISD2 inhibition exhibited tumor-suppressing effects in vivo associated with the induction of ferroptotic cell death in xenografts. These findings suggest that CISD2inhibition has tumor-suppressing effects on DLBCL by promoting ferroptotic cell death via the NRF2/SLC7A11/GPX4 pathway. Therefore, CISD2 holds promise as a viable candidate target for treating DLBCL.

YAP1 Overexpression Enhances the Aerobic Glycolysis Process via Suppression of EGLN2 in Pancreatic Ductal Adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases and has remarkably high mortality rates. In recent years, altered metabolism has been shown to contribute to the maintenance of pancreatic cancer malignancies. However, the molecular mechanism underlying glucose metabolism reprogramming remains elusive. The aim of this study was to elucidate the role of Yes-associated protein (YAP1), an important effector of the Hippo pathway, in the regulation of aerobic glycolysis in pancreatic cancer. Moreover, the contributions of YAP1 and its associated glycolytic enzymes to prognosis were assessed via The Cancer Genome Atlas (TCGA) dataset. YAP1 expression was silenced by short hairpin RNA (shRNA), and its effects on glycolytic activity and mitochondrial respiration were analysed via Agilent Seahorse XF Analysers. The effects of YAP1 on hypoxia-inducible factor-1α (HIF-1α) and its transcriptional activity on glycolytic genes were examined via shRNA-mediated silencing of YAP1. The underlying mechanism by which YAP1 controls the HIF-1α protein level was analysed by exploring the interaction between YAP1 and egg-laying-defective nine family (EGLN) members, which are well-established regulators of the HIF-1α protein level. Finally, the effects of YAP1, EGLN and glycolytic genes on prognosis were analysed via TCGA dataset. We found that silencing YAP1 expression inhibited anabolic glycolysis in pancreatic cancer cells. YAP1 was demonstrated to regulate the HIF-1α protein level, transcriptional activity and the expression of HIF-1α-targeted glycolytic genes. In-depth analysis demonstrated that EGLN2, a modulator of the HIF-1α protein level, was a direct target of YAP1. Low EGLN2 expression was associated with a poor prognosis. By analysing TCGA dataset and performing immunohistochemical staining, we demonstrated that YAP1 expression was negatively correlated with EGLN2 expression at the mRNA level and protein levels. The present study demonstrated that YAP1 positively regulates aerobic glycolysis by inhibiting EGLN2 expression, which results in an increased HIF-1α protein level and transcriptional activity. YAP1 was positively regulated and significantly correlated with HIF-1α-targeted glycolytic genes, including glucose transporter type 1(GLUT1), hexokinase2 (HK2) and lactate dehydrogenase A (LDHA). Elevated YAP1 expression and concomitant downregulation of EGLN2 contributed to poor survival in patients with pancreatic cancer. Our results suggest that YAP1 may be a promising predictive marker and treatment target for human pancreatic cancer.

Multi-method coamorphous systems of lumefantrine with alpha ketoglutaric acid: Comprehensive characterization, biological evaluation and stability analysis.

The Coamorphous systems (CAM) of lumefantrine (LMF) and alpha-ketoglutaric acid (KGA) were developed using three different methods to address the solubility and bioavailability limitations of LMF. Powder X-ray diffraction spectroscopy (PXRD) and differential scanning calorimetry (DSC) confirmed the complete amorphization of the three CAM by the halo pattern and glass transition temperature (Tg), respectively. Attenuated total reflectance-Fourier transform infrared spectroscopy (ATR-FTIR) and nuclear magnetic resonance spectroscopy (NMR) results indicated that intermolecular interactions existed in the three CAM. Solid-state molecular dynamics simulations revealed the different intermolecular disordered environments present in all three CAM. Solubility analysis showed 14.73×, 12.8× and 9.81× improvement in the liquid-assisted grinding-based coamorphous system (CAM LAG), solvent evaporation-based coamorphous system (CAM SE) and quench-cool-based coamorphous system (CAM QC), respectively, compared to LMF crystalline (LMF CRY). In the in-vitro dissolution experiment 2.63-, 2.16- and 2.17-times increments were observed in CAM LAG, CAM SE and CAM QC compared to LMF CRY, respectively. In-vivo pharmacokinetics study revealed 10.86-, 9.24- and 8.46- folds increments in Cmax of CAM LAG, CAM SE and CAM QC, respectively, compared to LMF CRY. All three CAM illustrated anti-cancer activity in the A549 lung cancer cell line. Molecular dynamics simulation of LMF and KGA with Epidermal growth factor receptor (EGFR), a target for lung cancer treatment, revealed good binding affinity and stability. Stability studies performed under accelerated storage (40 °C/75 % RH) and extreme environmental conditions indicated that all three CAM have good stability. Different methods based prepared CAM have shown different physicochemical properties, bioavailability and stability profiles. These findings suggest that LMF-KGA CAM effectively addresses the solubility and bioavailability challenges of LMF, potentially leading to better therapeutic outcomes in lung cancer treatment.

Design and Development of Novel Hybrids Based on Pyrrolo[2,1-f][1,2,4]Triazine and 1-(Methylpiperidin-4-yl) Aniline-Based Analogs: Exploring the Utility as Anticancer Agents via MERTK Inhibition.

Mer-tyrosine kinase (MERTK), a member of the AXL, TYRO3, and MERTK (TAM) family, is one of the promising targets for cancer treatment. It plays a key role in cancer cell survival and proliferation and regulates immune responses in cancer. The study aimed to rationally design and develop molecules considering the pharmacophoric requirements of MERTK using a multi-synthetic approach followed by the hybridization of individual pharmacophores. A hybrid drug design approach was employed by hybridization of pyrrolo[2,1-f][1,2,4]triazine and 1-(methylpiperidin-4-yl)aniline pharmacophoric systems to develop novel leads (1K1-1K5). The molecules were synthesized via a multi-step synthetic approach. The synthesized molecules were assessed for their pharmacological potential via cell viability, drug metabolism and pharmacokinetics (DMPK), and MERTK inhibition studies corroborated by in silico studies. IK5 was found to have an IC50 value of 0.36 μM towards A549, followed by 0.42 μM and 0.80 μM against MCF-7 and MDA-MB-231 cells, respectively. Further, the molecules were also analyzed for their microsomal stability and were found to be stable with better intrinsic clearance profiles. The molecules thus pave a strategy for developing novel MERTK inhibitors and their advance invitro and invivo assessment in the future.

Evaluation of Syndecan-1 Expression in Iraqi Patients with Papillary Thyroid Carcinoma

Papillary thyroid carcinoma (PTC) represents the most prevalent kind of thyroid gland cancer, making up around 80% of all occurrences of thyroid cancer. Evidence shows that Syndecan-1 (SDC-1) expression is lost in a number of benign and malignant epithelial neoplasms, although its expression profile in thyroid gland neoplasms is yet unknown. Therefore, the aim of this study was to assess SDC-1 expression in papillary thyroid carcinoma patients, as well as the relationship between age and gender and SDC-1 expression. To undertake a detailed investigation of SDC-1 in normal and malignant tissues, tissue sections were used to examine SDC-1 expression in 70 tissue samples, 50 distinct PTC (6 males and 44 females) and 20 normal tissue types (10 from each gender) as control. Ages in each group ranged from 20 to 60 years. The results showed a statistically different level of SDC-1 expression in patients and control. There was no significant relationship between SDC-1 expression and gender or age, in accordance with recent research findings which suggest that SDC- 1 might be exploited as a prognostic indicator or a target in cancer treatment in the future.

Ultra-high dose rate (FLASH) radiotherapy: revolutionizing tumor targeting and microenvironmental dynamics in cancer treatment.

Ultra-high dose rate (FLASH) radiotherapy: revolutionizing tumor targeting and microenvironmental dynamics in cancer treatment.

Integrated analysis of disulfidptosis-related genes SLC7A11, SLC3A2, RPN1 and NCKAP1 across cancers

Disulfidptosis, a newly identified form of regulated cell death associated with disruption of disulfide bond formation in the endoplasmic reticulum, involves the dysregulation of disulfidptosis-related genes (DRGs) that may contribute to cancer development and progression. However, the molecular mechanisms and clinical implications of DRGs in different cancer types remain poorly characterized. Therefore, in this comprehensive study, we investigated the expression, prognostic value, and functional roles of four recently identified DRGs (SLC7A11, SLC3A2, RPN1, and NCKAP1) across various cancers. Especially, in clinical samples of glioblastoma, we found that RPN1 was significantly correlated with patient survival. Through mutation landscape analysis, we identified diverse missense mutations in these DRGs, with NCKAP1 exhibiting the highest mutation frequency (5.9% in skin cutaneous melanoma). Additionally, we observed positive correlations between these DRGs and tumor stemness (DNAss DNA stemness score and RNAss RNA stemness score) as well as RNA modifications, particularly m6A modification, in several cancer types. Furthermore, high expression of SLC7A11, RPN1, and NCKAP1 was positively associated with infiltration of T-helper type 2 (Th2) cells in various cancers, while high expression of SLC7A11, SLC3A2, and RPN1 correlated with tumor mutational burden (TMB) in 10, 4, and 8 tumor types, respectively. Utilizing a protein–protein interaction network, we identified the RHO GTPases Activate WASPs and WAVEs pathway as significantly enriched, suggesting the involvement of these DRGs in cancer-related signaling pathways. Collectively, our findings provide novel insights into the molecular mechanisms and clinical implications of DRGs in pan-cancer, highlighting their potential as biomarkers and therapeutic targets for cancer treatment.

ERBB2 comprehensive profiling and prognostication in Stage III Colon Cancer: Findings from PETACC8 and IDEA-France cohorts

ERBB2-pathway activation, through amplification or activating mutations, represents a new target for colon cancer (CC) treatment. We compared molecular methods to the gold-standard for assessing ERBB2 status and determined the prognostic value of ERBB2 amplification, mutations, and expression using data from two phase III trials involving nearly 3,000 stage III CC patients. In the PETACC8 trial, IHC/FISH, DNA, and RNA analysis were performed on 1813, 1719, and 1733 samples, respectively. In the IDEA-France trial, DNA and RNAseq were performed on 1129 and 1263 samples. The breast cancer SCAN-B cohort (n=3409) served as an external reference. A new molecular ERBB2-amplified status was defined using ERBB2 NGS-score, RNAseq expression, and clustering based on ERBB2 neighboring gene expression. Concordance between diagnostic techniques and the association between time-to-recurrence (TTR) and ERBB2-status were evaluated. The prevalence of the molecular ERBB2-amplified group was 1.85% in PETACC8 and 1.5% in IDEA-France, with a concordance of 0.81 (95% CI [0.70-0.92]) with the gold-standard IHC/FISH method in PETACC8. A non-linear relationship was observed between TTR and ERBB2-expression, with extreme groups showing a less favorable prognosis (P<.0001) in both colon and breast cancers. Patients with molecular ERBB2-amplified status or mutations had the poorest prognosis, followed by low-expression and intermediate-expression groups (3-year TTR 67.0%, 71.2%, and 77.9%, respectively). In multivariate analysis, the low-expression group had a significantly shorter TTR (HR=1.28; 95%CI [1.07-1.52]). The molecular definition of ERBB2-status could represent a cost-effective alternative in stage III CC. ERBB2 alterations and low RNA expression significantly reduce TTR, highlighting the complex role of ERBB2.

Unveiling the Role of Mechanistic Target of Rapamycin Kinase (MTOR) Signaling in Cancer Progression and the Emergence of MTOR Inhibitors as Therapeutic Strategies.

The mechanistic target of rapamycin kinase (MTOR) is pivotal for cell growth, metabolism, and survival. It functions through two distinct complexes, mechanistic TORC1 and mechanistic TORC2 (mTORC1 and mTORC2). These complexes function in the development and progression of cancer by regulating different cellular processes, such as protein synthesis, lipid metabolism, and glucose homeostasis. The mTORC1 complex senses nutrients and initiates proliferative signals, and mTORC2 is crucial for cell survival and cytoskeletal rearrangements. mTORC1 and mTORC2 have therefore emerged as potential targets for cancer treatment. Several mTOR inhibitors, including rapamycin and its analogs (rapalogs), primarily target mTORC1 and are effective for specific cancer types. However, these inhibitors often lead to resistance and limited long-term advantages due to the activation of survival pathways through feedback mechanisms. Researchers have created next-generation inhibitors targeting mTORC1 and mTORC2 and dual PI3K/mTOR inhibitors to address these difficulties. These inhibitors demonstrate enhanced anti-tumor effects by simultaneously disrupting multiple signaling pathways and show promise for improved and long-lasting therapies. However, development of resistance and adverse side effects remain a significant obstacle. Recent additions known as RapaLinks have emerged as a boon to counter drug-resistant cancer cells, as they are more potent and provide a more comprehensive blockade of mTOR signaling pathways. This Review combines current research findings and clinical insights to enhance our understanding of the crucial role of mTOR signaling in cancer biology and highlights the evolution of mTOR inhibitors as promising therapeutic approaches.

Computational discovery of novel GPX4 inhibitors from herbal sources as potential ferroptosis inducers in cancer therapy

Ferroptosis, a cell death regulation process dependent on iron levels, represents a promising therapeutic target in cancer treatment. However, the scarcity of potent ferroptosis inducers hinders advancement in this area. This study addresses this gap by screening the PubChem database for compounds with favorable ADMET properties to identify potential GPX4 inhibitors. A structure-based virtual screening was conducted to compare binding affinities of selected compounds to that of RSL3. The candidates—isochondrodendrine, hinokiflavone, irinotecan, and ginkgetin—were further analyzed through molecular dynamics (MD) simulations to assess their stability within the GPX4-ligand complexes. The computed binding free energies for RSL3, isochondrodendrine, hinokiflavone, irinotecan and ginkgetin were −80.12, −107.31, −132.03, and −137.52 and −91.11 kJ/mol, respectively, indicating their significantly higher inhibitory effects compared to RSL3. These findings highlight the potential for developing novel GPX4 inhibitors to promote ferroptosis, warranting further experimental validation.