Epidermal Growth Factor Receptor Family Research Articles

Design and Synthesis of Novel Spiro [Chromane‐2,4′‐Piperidin]‐4‐One Derivatives: Anti‐Proliferative Investigation and Molecular Docking Studies

AbstractChemists around the globe are extensively working for remedial solutions to cancer, one of the greatest health hazards. We have synthesized twenty‐three novel spiro [chromane‐2,4′‐piperidin]‐ 4 ‐one derivatives (KBS and KMS series of analogues) as part of our ongoing research to combat this deadly disease, and confirmed their structures using 1H NMR, 13C NMR, HRMS, and FT‐IR. Furthermore, we employed single‐crystal XRD to identify the compound structures of KBS4 and KMS10. We have tested the compounds on the cell line such as MCF‐7; U87‐MG; SCC‐25; and HEK‐293T, via WST‐1 assay. Eight compounds showed IC50 values ranging 3.9–10 μM; against the cell line MCF‐7. The best compounds of all were KMS9 (IC50=3.83 μM), KMS5 (IC50=4.14 μM), and KBS8 (IC50=8.24 μM), which promoted apoptosis in MCF‐7 cells. KMS5 and KMS9 compounds showed G1 cell cycle arrest, while compound KBS8 showed G2 cell cycle arrest. Insilco ADME studies were carried out. Molecular docking and dynamics experiments showed how KMS5, KMS9, and KBS8 bind to the active region of the EGFR family – a group of receptor tyrosine kinase (RTK) proteins (PDB ID: 7JXP, 2.16 Å). Further structural modifications of the KMS5, KMS9, and KBS8 may improve their activity against breast cancer.

Structural Basis of Activity of HER2-Targeting Construct Composed of DARPin G3 and Albumin-Binding Domains.

Non-immunoglobulin-based scaffold proteins (SPs) represent one of the key therapeutic target-specific and high-affinity binders in modern medicine. Among their cellular targets are signaling receptors, in particular, receptor tyrosine kinases, whose dysfunction leads to the development of cancer and other serious diseases. Successful applications of SPs have been reported for HER receptor type 2 (HER2), a member of the human epidermal growth factor receptor family that regulates cell growth and differentiation. To extend the blood residence of SPs and prevent their high accumulation in the kidneys, these proteins are often fused with serum albumin. Promising results for HER2-binding activity were obtained for SP G3 from the DARPins (Designed Ankyrin Repeat Proteins) family fused with an albumin-binding domain (ABD). Interestingly, the detected HER2-G3 binding strongly depended on the position of the G3 module in the sequence of the constructs. Further improvement of these constructs for biomedical applications requires deciphering the molecular mechanism responsible for this effect. Here, we investigate the structural and dynamic aspects of ABD-G3 and G3-ABD chimeras using NMR spectroscopy and molecular modeling. Based on biophysical data, we come to the conclusion that extensive inter-domain contacts form in both constructs, although their binding interfaces and complex stability are somewhat different. Also, it is shown that the domain linker plays an important role-it limits the accessibility of the detected protein-protein binding sites, depending on the order of the domains in the chimeric molecules. These results create a solid structural basis for the rational design of new effective SP constructs targeting the signaling receptors in cells.

Tyrosine kinase inhibitors in the treatment of leptomeningeal carcinomatosis.

Leptomeningeal carcinomatosis (LMC) is a devastating complication of advanced cancers, such as lung cancer and breast cancer, which is usually indicative of a poor prognosis. The current treatments for LMC include palliative care, with others aiming to prolong survival and relieve neurological symptoms. Traditional treatments for LMC include radiotherapy, systemic chemotherapy, and intrathecal injection. Furthermore, the application of molecularly targeted agents, such as antiepidermal growth factor receptor (anti-EGFR), antihuman epidermal growth factor receptor 2 (anti-HER2), and anti-PD-1 monoclonal antibody, have prolonged the survival of LMC patients. Targeted therapy with tyrosine kinase inhibitors has also been proven to be an effective treatment. Tyrosine kinases can be overactive or expressed at high levels in some cancer cells; therefore, the use of tyrosine kinase inhibitors may prevent the activation of tumor-related pathways, preventing cancer cell growth. The EGFR family are cell surface receptors directly related to tumor occurrence with tyrosine kinase activity; it is the most widely used target for tyrosine kinase inhibitors in the treatment of LMC. In this review, we introduced the clinical manifestation and diagnostic criteria of LMC, clarified the treatment mechanism of tyrosine kinase inhibitors for LMC with mutations in EGFR, HER2, or anaplastic lymphoma kinase, reviewed the current application of various generation tyrosine kinase inhibitors in patients with LMC, and discussed new clinical trials and the future directions of tyrosine kinase inhibitor therapy.

Abstract B033: MUC16 - Potential Target for Antibody-based Immunotherapy in Pancreatic Cancer

Abstract Pancreatic ductal adenocarcinoma (PDAC) is the most devastating and lethal cancer. PDAC patients with the current standard of care produce dismal overall survival benefits with high toxicities. Thus, there is an unmet clinical need to develop targeted therapeutics against PDAC. Approximately 50 to 70% of PDAC patients overexpress MUC16, which is associated with disease progression, metastasis, drug resistance, and poor patient survival. We demonstrated that MUC16 enhances PDAC tumor growth via binding and activating epidermal growth factor (EGF) receptor family members and its downstream target PI3K/AKT signaling pathways. Here, we show the efficacy of humanized anti-MUC16 antibody (huAR9.6) against MUC16-positive PDAC. Methods: We tested the in vitro efficacy of humanized anti-MUC16 antibody (huAR9.6) against MUC16+ PDAC cells, patient-derived xenografts (PDXs), and patient-derived organoids (PDOs). We evaluated the in vivo therapeutic efficacy of the huAR9.6 antibody in MUC16+ PDAC cells implanted in subcutaneous and orthotopic tumor models. Fucosylated and afucosylated huAR9.6 induced direct tumor-killing activity was evaluated by antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) with MUC16 positive PDAC cells. Results: Treatment with huAR9.6 reduced the in vitro growth, migration, invasion, and clonogenicity of MUC16+ PDAC cells and patient-derived organoids (PDOs). HuAR9.6 blocked MUC16-mediated ErbB and AKT activation in PDAC, PDOs, and PDX-derived cells. HuAR9.6 treatment induces ADCC and CDC against MUC16+ cells. Removing fucose residue on the N-glycans of the huAR9.6-IgG substantially increased huAR9.6’s ADCC activity. More importantly, huAR9.6 treatment caused PDAC regression in subcutaneous and orthotopic tumor models. Conclusion: The results of this study validate the translational therapeutic potential of huAR9.6 against MUC16-positive PDACs (detected in ∼ 50-70% of patients). Citation Format: Cory L Brooks, Prakash Radhakrishnan. MUC16 - Potential Target for Antibody-based Immunotherapy in Pancreatic Cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B033.

Knockdown and Overexpression Experiments to Investigate the Inhibitory Mechanism of Fuzheng Xiaozheng Prescription, an Effective Chinese Herbal Formula for the Clinical Treatment of Hepatocellular Carcinoma.

Fuzheng Xiaozheng prescription (FZXZP) is an effective formula for the treatment of different kinds of chronic liver diseases. However, its potential molecular mechanisms in treating hepatocellular carcinoma (HCC) have not been investigated thoroughly. The aim of this study is to elucidate the targets and intrinsic mechanisms of FZXZP and their active components for the treatment of HCC. The efficacy of FZXZP against HCC was clarified through a rat HCC model and HCC cell culture. Network pharmacology and molecular docking were utilized to predict the mechanism of action and effector components of FZXZP. The key mechanism and targets were verified by the construction of overexpression and knockout cell models. The results showed that FZXZP greatly delayed the development of HCC in vivo experiments, as evidenced by biochemical evaluations, H&E analyses and growth inhibition of HCC. FZXZP dramatically inhibited cell viability and proliferative capacity and induced the apoptosis of hepatoma cells in vitro. Moreover, network pharmacology analyses demonstrated that the EGFR family and apoptosis-related targets were found to be the most significant in bioinformatics analysis. Furthermore, the EGFR/STAT3 signal axis might be the most likely target of FZXZP in anti-HCC due to the fact that it could be down-regulated by FZXZP with an upward trend of Bax, Caspase-3, Caspase-8, Caspase-9 and an inverse trend of Bcl2. Importantly, the above targeted signal axis was finally validated by our knockdown and overexpression analyses. Meanwhile, flow cytometry and TUNEL staining also revealed that FZXZP significantly induced apoptosis in the EGFR-overexpressing HCC cell line. The molecular docking results revealed that the key effector components of FZXZP that exerted the above regulatory roles were wogonin and glycitein. All of these results suggest that FZXZP could significantly delay HCC development by inhibiting proliferation and promoting apoptosis of HCC cells, and the EGFR/STAT3 signal axis might be a critical signal axis of FZXZP in suppressing HCC progression.

Amiloride Sensitizes Prostate Cancer Cells to the Reversible Tyrosine Kinase Inhibitor Lapatinib by Modulating ERBB3 Subcellular Localization.

Neoadjuvant therapy (NAT) has been studied in clinically localized prostate cancer (PCa) to improve the outcomes from radical prostatectomy (RP) by 'debulking' of high-risk PCa; however, using androgen deprivation at this point risks castration resistant PCa (CRPC) clonal proliferation with potentially profound side effects such as fatigue, loss of libido, hot flashes, loss of muscle mass, and weight gain. Our goal is to identify alternative NAT that reduce hormone sensitive PCa (HSPC) without affecting androgen receptor (AR) transcriptional activity. PCa is associated with increased expression and activation of the epidermal growth factor receptor (EGFR) family, including HER2 and ErbB3. Dimerization between these receptors is required for activation of downstream targets involved in tumor progression. The FDA-approved HER2 inhibitor lapatinib has been tested in PCa but was ineffective due to continued activation of ErbB3. We now demonstrate that this is due to ErbB3 being localized to the nucleus in HSPC and thus protected from lapatinib which affect membrane localized HER2/ErbB3 dimers. Here, we show that the well-established, well-tolerated diuretic amiloride hydrochloride dose dependently prevented ErbB3 nuclear localization via formation of plasma membrane localized HER2/ErbB3 dimers. This in turn allowed lapatinib inactivation of these dimers via inhibition of its target HER2, which dephosphorylated downstream survival and proliferation regulators AKT and ERK1/2. Amiloride combined with lapatinib significantly increased apoptosis but did not affect AR transcriptional activity. Thus, our data indicate that a combination of amiloride and lapatinib could target HSPC tumors without problems associated with androgen deprivation therapy in localized PCa.

A Comparison of Immunohistochemical Expression of Epidermal Growth Factor Receptor and Human Epidermal Growth Factor Receptor 2 in Dental Follicles with Different Radiographic Sizes.

Odontogenic cysts and tumors develop from the dental follicle of asymptomatic impacted teeth. Odontogenic tissues express the epidermal growth factor receptor family (EGFR), which mediates cell proliferation, survival, and neoplastic differentiation. The present study aimed to compare the immunohistochemical expression of EGFR and human epidermal growth factor receptor 2 (HER2) in the dental follicle of impacted wisdom teeth with normal and abnormal radiographic size. In this analytical study, immunohistochemical staining of EGFR and HER2 was performed on 30 normal and 30 abnormal follicles of impacted third molars. Follicles with a width of <2.5 mm were considered normal, whereas those with a width of ≥2.5 mm were regarded as abnormal. The immunoreactive score (IRS) was used to report the expression levels of EGFR and HER2. The obtained data were analyzed using SPSS software. Age and sex were compared in normal and abnormal groups with independent t test and Chi square test, respectively. P<0.05 was considered statistically significant. The EGFR and HER2 overall expression was high in all normal and abnormal follicles. The comparison of the percentage of stained cells and intensity of EGFR and HER2 staining in normal and abnormal follicles were not significantly different (P=0.73, P=0.63, P=0.95, respectively). Due to the high expression of EGFR and HER2 in normal and abnormal follicles, as well as the lack of significant differences in these two groups, the radiographic size of dental follicles might not indicate the potential capabilities of their cells, and more research in this field is recommended.

Characteristics of sphingomyelin metabolism in the MCF7 and BT474 radiotherapy‑resistant HER2‑positive breast cancer cell lines.

Breast cancer is the most common cancer globally in terms of incidence. This cancer is classified into subtypes based on histological or immunological characteristics. HER2-positive cases account for 15-25% of breast cancer cases, and one of the first events in breast carcinogenesis is HER2 upregulation. Furthermore, HER2 expression increases the detection rate of metastatic or recurrent breast cancers by 50-80%. The epidermal growth factor receptor family includes HER2, which is a transmembrane receptor protein. In our previous case report, patients who were resistant to anti-HER2 monoclonal antibody therapy, chemotherapy and radiotherapy had higher concentrations of phospholipid metabolites such as phosphatidylcholine and sphingomyelin (SM), which was associated with cancer recurrence progression. To better understand the relationship between radiotherapy resistance and SM expression, breast cancer cell lines with and without HER2 expression (MCF7 and BT474) after exposure to ionizing radiation (IR) were examined. In the cell culture supernatant, similar levels of SM in MCF7 cells were identified after 1-4 Gy exposure. However, SM levels in BT474 cells were upregulated compared with those of in the control group. Intracellular SM levels were upregulated in BT474 cells exposed to 1 and 4 Gy compared with the non-irradiated control group. Furthermore, significantly increased mRNA expression levels of sphingomyelin synthase 2 (SGMS2) in BT474 cells exposed to IR were observed compared with those in nonirradiated cells; however, the SGMS2 levels in MCF7 cells did not differ significantly among the 0, 2 and 4 Gy groups. These findings suggested that a higher dose of IR induced the secretion of SM and its associated gene expression in HER2-positive breast cancer cells.

Structural biology of HER2/ERBB2 dimerization: mechanistic insights and differential roles in healthy versus cancerous cells

Aim: Present study was done to understand the dimerization of HER2/ERBB2 in normal and cancer cells using in-silico study. Methods: Pathway analysis was done using Reactome. Structure of HER2/ERBB2 protein was obtained from PDB database, and using Schrödinger software protein structure was analysed and dimerization was done. Results: In normal cells, HER2/ERBB2 is present at low levels and forms a stable complex with HSP90 (heat shock protein 90), CDC37 (cell division cycle 37), and ERBIN (an adaptor protein of the HER2/ERBB2 receptor). HER2/ERBB2 lacks a ligand-binding site, so it cannot bind ligands to activate HER2/ERBB2 signaling directly. Instead, it heterodimerizes with other EGFR family members, using their ligand-binding sites to activate cell proliferation signaling cascades. In cancer, overexpression of HER2/ERBB2 leads to ligand-independent activation of signaling through dimerization. During this process, HER2/ERBB2 dissociates from the HSP90 complex. Normally, HSP90 helps to correct misfolded and aggregated proteins, but it fails to correct mutated HER2/ERBB2 in cancer cells. Conclusions: This discussion focuses on the structural changes that HER2/ERBB2 undergoes, particularly in the form of homodimers, under normal and cancerous conditions. This analysis highlights the mutated state of HER2/ERBB2 and the role of HSP90 in this context. Notably, a single-point mutation outside a protein’s active site can significantly alter its structure. This is a critical consideration in drug discovery, underscoring the need to evaluate the entire protein conformation during simulations.

Nanoparticle-based targeted therapy through EGFR tyrosine kinase inhibitors and their recent advances in lung cancer therapy

The emergence and subsequent advancement of nanotechnology in recent years have greatly benefited the healthcare sector, particularly in the treatment of cancer. As per study, major fatalities are related to the lung cancer. For many years, oral tyrosine kinase inhibitors (TKIs) against the epidermal growth factor receptor (EGFR) family of receptors have been used in the clinic to treat human malignancies, although they observed some very serious adverse effects in the treatment of lung cancer, especially in non-small cell lung cancer (NSCLC). Despite EGFR-TKIs’ exceptional qualities as small-molecule targeted medications, their applicability is nevertheless limited by their poor solubility, inconsistent oral bioavailability, high daily dose needs, high plasma albumin binding propensity, and initial/acquired drug resistance. Article’s purpose is to investigate EGFR-TKI’s effects on lung cancer and get around some of its drawbacks, nanotechnology will be an innovative strategy. An effective tool to increase the effectiveness of these pharmaceuticals is nanotechnology by methods other than oral. This article signifies that a range of nanomedicine delivery systems have been developed to effectively distribute EGFR-TKIs with improved drug release kinetics and tissue-targeting capacity. This review article intends to present information regarding lung cancer and EGFR relation, mechanism of recently approved EGFR-TKI’s targeted therapy, an updated landscape of EGFR-TKIs and their clinical status over lung cancer, advantages and disadvantages of nanotechnology, and new breakthroughs in nano-delivery which mentioned as a significantly better over traditional drug chemotherapy and delivery.

A Comprehensive Review of HER2 in Cancer Biology and Therapeutics.

Human epidermal growth factor receptor 2 (HER2), a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, plays a crucial role in cell proliferation, survival, and differentiation. Aberrant HER2 signaling is implicated in various cancers, particularly in breast and gastric cancers, where HER2 overexpression or amplification correlates with aggressive tumor behavior and poor prognosis. HER2-activating mutations contribute to accelerated tumorigenesis and metastasis. This review provides an overview of HER2 biology, signaling pathways, mechanisms of dysregulation, and diagnostic approaches, as well as therapeutic strategies targeting HER2 in cancer. Understanding the intricate details of HER2 regulation is essential for developing effective targeted therapies and improving patient outcomes.

The Evolving Paradigm of Antibody-Drug Conjugates Targeting the ErbB/HER Family of Receptor Tyrosine Kinases.

Current therapies targeting the human epidermal growth factor receptor (HER) family, including monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs), are limited by drug resistance and systemic toxicities. Antibody-drug conjugates (ADCs) are one of the most rapidly expanding classes of anti-cancer therapeutics with 13 presently approved by the FDA. Importantly, ADCs represent a promising therapeutic option with the potential to overcome traditional HER-targeted therapy resistance by delivering highly potent cytotoxins specifically to HER-overexpressing cancer cells and exerting both mAb- and payload-mediated antitumor efficacy. The clinical utility of HER-targeted ADCs is exemplified by the immense success of HER2-targeted ADCs including trastuzumab emtansine and trastuzumab deruxtecan. Still, strategies to improve upon existing HER2-targeted ADCs as well as the development of ADCs against other HER family members, particularly EGFR and HER3, are of great interest. To date, no HER4-targeting ADCs have been reported. In this review, we extensively detail clinical-stage EGFR-, HER2-, and HER3-targeting monospecific ADCs as well as novel clinical and pre-clinical bispecific ADCs (bsADCs) directed against this receptor family. We close by discussing nascent trends in the development of HER-targeting ADCs, including novel ADC payloads and HER ligand-targeted ADCs.

From Intractable to Treatable: Milestones and Horizons in the Management of HER2+ Breast Cancer

The human epidermal growth factor receptor 2 (HER2) is a member of the epidermal growth factor receptor (EGFR) family that initiates various signalling pathways that control cell proliferation and tumourigenesis. Historically, approximately 15% of breast cancers have been characterized by overexpression or amplification of HER2, known as “HER2+” breast cancers. This subtype has been associated with an adverse prognosis, along with a high risk of recurrence and worse survival outcomes. However, with the discovery and subsequent development of HER2‑targeted therapies, the clinical course of HER2+ breast cancers has fundamentally changed. Optimizing therapeutic strategies using existing and emerging HER2-targeted therapies to build upon these advances remains a major priority for clinical development and treatment delivery. In 1998, the American Food and Drug Administration (FDA) and Health Canada approved trastuzumab, the first HER2-targeted therapy. Trastuzumab, a monoclonal antibody that binds to the HER2 receptor, has demonstrated clinical activity and improved outcomes in patients with metastatic HER2+ breast cancer when combined with chemotherapy. Following soon after, the first trial of adjuvant trastuzumab (HERA) demonstrated improvements in outcomes when combined with chemotherapy for early HER2+ breast cancer. More than 25 years after its first approval, trastuzumab retains a central role in the treatment of both early and advanced HER2+ breast cancer and has provided a backbone for both new therapeutic combinations (eg. with small molecule inhibitors of HER2) and new classes of therapeutic agents (antibody drug conjugates [ADC]). These successors of trastuzumab are currently redefining the HER2+ treatment landscape in both advanced and early breast cancer.

Current and Emerging Treatment Options for HER2‑Positive Gastroesophageal Cancer

Gastroesophageal cancer (GEC) is the fifth most common cancer and the second most common cause of cancer-related mortality, with 1.3 million annual deaths worldwide. The global incidence is increasing, particularly among younger patients. GEC can be classified into subtypes based on anatomic location, histology, molecular characteristics, or tumour biology and genomics. In approximately 20% of all GECs overexpression of HER2 is identified. The landscape of treatment options in this patient population is evolving rapidly. This review summarizes the progress of HER2-directed therapies for advanced disease and highlights future directions in targeting the disease. The epidermal growth factor receptor (EGFR) family of transmembrane tyrosine kinase receptors, EGFR/HER1, HER2/neu, HER3, and HER4, all have an extracellular ligand-binding domain, lipophilic transmembrane domain, and an intracellular domain with tyrosine kinase activity, binding to these receptors results in activation of downstream RAS/MAPK and PI3K/AKT pathways. In turn, this induces cell proliferation, differentiation, migration, and survival. The phase III Trastuzumab for Gastric Cancer (ToGA) trial reported the incidence of HER2-positive gastric cancer to be 22%. Therefore, targeting HER2 and its downstream signaling pathways holds important potential as a therapeutic strategy. Figure 1 illustrates potential targeting mechanisms that will be discussed in this review.

A bibliometric and visualization analysis of research trends and hotspots on targeted therapy for breast cancer from 2003 to 2022.

Breast cancer is a significant public health issue, exhibiting the most pronounced occurrence and fatality rates among malignant neoplasms globally. Targeted therapy is a medical intervention that focuses on specific molecular markers. This study aims to investigate and evaluate the current research trends and directions in the field of targeted therapy for breast cancer using bibliometric analysis. The Web of Science database was utilized to retrieve relevant articles published between 2003 and 2022. The VOSviewer software and Bibliometrix package in the R language were employed to conduct co-occurrence and clustering analyses of authors, countries, institutions, journals, references, and the CiteSpace tool was utilized for keyword burst detection. A total of 2,258 articles were included and the annual number of publications increased rapidly. The most prolific country on this topic was the USA (n=898, 39.77%) and the University of Texas MD Anderson Cancer Center published most papers (n=93). Dennis J. Slamon and Gabriel N. Hortobagyi stood out in the field, with Dennis J. Slamon leading in terms of co-citations(n=653) and Gabriel N. Hortobagyi topping the list in terms of published articles(n=18). The most productive journal was Breast Cancer Research and Treatment and the most cited journal was Journal of Clinical Oncology. The clustering of keywords indicated that the primary focus of researches in the past two decades was on the development and clinical evaluation of tumor-targeted drugs associated with the epidermal growth factor receptor (EGFR) family signaling pathway, and explored mechanisms related to biological behavior of breast cancer. Keywords co-occurrence and burst analysis identified current research hotspots and potential research trends. This study employed bibliometric analysis to examine research on targeted therapy for breast cancer over a span of 20 years, and identified development trends of research and elucidated potential research trajectories in the domain of this topic. This study helps in the identification of prospective collaborators and partner institutions for researchers.

DECIPHERING HUMAN ESTROGEN RECEPTOR-2 INHIBITOR FROM Momordica charantia: COMPUTATIONAL MODELS AGAINST BREAST CANCER.

HER-2, or Human Epidermal Growth Factor Receptor-2, is a constituent of the epidermal growth factor receptor family, possessing tyrosine kinase properties. Its over-expression has been correlated with breast cancer. On the other hand, the pharmacological potential of Momordica charantia has been attributed to the phytocompounds. Herein, the inhibiting potential of phytocompounds from M. charantia against HER-2 was investigated using computational approaches. Maestro Schrodinger software (2021 v 12.1) was used to perform molecular docking, molecular mechanics generalized Born surface area (MM/GBSA), and pharmacokinetics prediction of a hundred phytocompounds from M. charantia against HER-2. The result revealed that among the phytocompounds, ve (5) showed promising inhibitory potential comparable to the standard drug, Getinib. The MM/GBSA result showed that Rutin, Quercetin, Isoquerrcitrin, Folic Acid, and riboavin formed a more stable complex with HER-2 than Getinib. The pharmacokinetics prole of the hit compounds showed that the hit compounds except riboavin violated two or more of Lipinski's rule of ve. In conclusion, the bioactive compounds found in M. charantia could potentially act as primary candidates for the creation of effective inhibitors targeting HER-2 in the treatment of breast cancer.

A set of molecular biomarkers as an indicator of cancer risk.

e12563 Background: Biomarkers are molecular indicators of a biological status and are often used to determine the presence or absence of cancer Molecular changes in both in of cancer cells and their surrounding environment including, blood other body fluids, and tissues that react to the cancer provide biomarker materials that may be effective predictor of disease risk or disease outcome. Effective biomarkers for the disease associated risk and early detection of cancer improves potential patient outcome. An emerging theme is to develop multi-omics panels of biomarker with sufficient sensitivity and specificity for the pre-symptomatic detection of cancer. We applied approximately 300 genomics and proteomics-based genomics (PbG) biomarkers, to identify a panel of biomarkers associated with different types of cancers using patient and donor RNA samples collected from platelets Platelet RNA mirrors the RNA of nucleated cells and can be an important indicator of tissue states particularly in under pro-inflammatory conditions [PMC9555784]. Methods: Publicly available RNA-seq data of N = 2351 blood platelet samples, (including n= 390 asymptomatic controls) from 18 different tumor types was analyzed to identify the panel of biomarkers associated with highest risk cancers. Approximately 300 genomic and PbG signatures (developed from gene expression-based signatures on patients stratified according to protein expression (IHC) and survival. The predictive value of each gene signature (including commercial once ROR, OncotypeDx, etc.) was evaluated by logistic regression modeling in univariate and multivariate settings. Results: Out of 300 biomarkers, we found a set of PbG biomarkers including ratio of BRG1 expression between nuclear and cytoplasm, cytoplasmic C-terminal-binding protein 2 (CtBP2) in express in cytoplasm and ratio of nucleus and cytoplasm, Nucleus Tripartite motif-containing 28 (TRIM28), Vascular endothelial growth factor (VEGF), Mitogen-activated protein kinases (MAPK), androgen receptor (AR) express in Nuclear vs cytoplasm, Glycoprotein 78 (Gp78) in cytoplasm, E2F3, and a member of the epidermal growth factor (EGF) receptor family (ERBB2) are highly predictive (0.77 (0.76 ~ 0.79)) of cancer associated risk on a multivariate training/validation setting. The BRG1 biomarker has the highest odds ratio (11.33) within model, known for coordinating and maintaining key signaling pathways that promote oncogenesis in different cancer types including leukemia, breast, and prostate cancer. Cancer Risk model = 3.4 - 1.01 ERBB2 + 0.3 GP78_Cyto - 3.2 AR_Nucl + 0.7 CtBP2_NucVsCyto - 0.3 E2F3 - 0.99 AR_NucVsCyto + 0.87 VEGF - 1.9 MAPK + 2.43 BRG1_NucVsCyto + 1.35 TRIM28_Nucl + 1.23 CtBP2_Cyto. Conclusions: Utilizing novel genomic, and proteomic technologies, risk prediction and early detection of cancer could identify patients at a time when outcomes are superior and treatment is manageable. Further evaluation of this model is recommended.

Synergistic Effects of Neratinib in Combination With Palbociclib or Miransertib in Brain Cancer Cells.

Aberrant expression and activation of epidermal growth factor receptor (EGFR) resulted in approval of several forms of EGFR inhibitors in the treatment of patients with a wide range of epithelial cancers. However, no EGFR inhibitor has yet been approved for the treatment of patients with brain cancer, indicating that targeting EGFR alone may not be sufficient in some patients. In this study, we investigated the role of all members of the EGFR family, other growth factor receptors, cell-cycle proteins, and downstream cell signaling pathways (e.g., mitogen-activated protein kinase (MAPK), serine/threonine protein kinase (AKT), signal transducer and activator of transcription (STAT3), Src, Abelson murine leukemia viral oncogene homolog (Abl)) on the growth of a panel of human brain cancer cell lines (HBCCLs). We examined the growth response of HBCCLs to treatment with 17 targeted agents compared to two cytotoxic drugs. Of the targeted agents, the irreversible pan-human epidermal growth factor receptor (HER) inhibitors neratinib and afatinib were more effective than erlotinib and lapatinib at inhibiting the growth of all HBCCLs, and the cyclin-dependent kinase (CDK)1/2/5/9 inhibitor dinaciclib was the most potent targeted agent. We found that treatment with Src/Abl/c-kit inhibitor dasatinib, signal transducer and activator of transcription (STAT3) inhibitor stattic, Abl/platelet-derived growth factor receptor (PDGFR)α/vascular endothelial growth factor (VEGFR)2/fibroblast growth factor receptor (FGFR)1 inhibitor ponatinib, and the tropomyosin receptor kinase (TRK)/ROS proto-oncogene 1 receptor tyrosine kinase (ROS)/anaplastic lymphoma kinase (ALK) inhibitor entrectinib, also inhibited the growth of all HBCCLs. Interestingly, these agents were more effective in inhibiting growth of HBCCLs when proliferating at a slower rate. In addition to inhibiting the proliferation of HBCCLs, treatment with neratinib, dinaciclib, dasatinib, stattic and trametinib inhibited the migration of brain tumor cell line A172. Notably, we found that treatment with neratinib in combination with palbociclib (CDK4/6 inhibitor), or miransertib (AKT1/2/3 inhibitor) resulted in synergistic growth inhibition of all HBCCLs. Our results support that repurposing drugs like neratinib in combination with the palbociclib or miransertib may be of therapeutic potential in brain cancer and warrants further investigations.

Gene Editing for Unraveling the Regulatory Role of a HER2-Associated Enhancer with lncRNA GAS5 and Related Genes in Breast Cancer Cells

Background: The HER2/neu gene belongs to the epidermal growth factor receptor (EGFR) family and encodes a 185 kDa protein with tyrosine kinase activity. HER2 amplification or overexpression has been associated with tumorigenesis and cancer progression, notably in breast cancer (BC). The long non-coding RNA GAS5 has been recognized as a tumor suppressor in BC, promoting apoptosis and inhibiting cell proliferation. Moreover, GAS5 regulates key signaling pathways in breast cancer, including PI3K/AKT/mTOR and PTEN signaling. The PI3K/AKT pathway is critical in various cancer processes, such as proliferation, apoptosis, invasion, and drug resistance. Breast cancer stem cells (BCSCs) and stemness genes also contribute to tumor growth and therapy resistance. Therefore, targeting key regulatory regions in the HER2 gene could offer potential therapeutic strategies. Objectives: In this study, we aimed to investigate the regulatory role of a putative enhancer located in the HER2 gene in the 17q12 region (GH17J039694; we referred to it as Her2-Enhancer1 in our previous study) on HER2 variants and genes that are connected to it through different pathways. Methods: We analyzed the effects of enhancer knockout on HER2 variants, GAS5, PTEN, and stemness genes in HER2-positive and HER2-negative breast cancer cells using the CRISPR/Cas9 system and real-time PCR. Results: Our results showed significantly reduced HER2 variant expression in both cell lines after genetic editing. Furthermore, the expression of some other target genes was affected, including GAS5, P53, and PTEN. Interestingly, we observed altered expression of stemness genes like NANOG, SOX2, and OCT4, indicating possible implications for cancer stem cell properties. Conclusions: Our study highlights the potential regulatory role of the studied region as an enhancer in the HER2 gene and sheds light on its influence on various cancer-related pathways, providing valuable insights into breast cancer pathogenesis and potential therapeutic targets.

Kinase Inhibitors and Kinase-Targeted Cancer Therapies: Recent Advances and Future Perspectives

Over 120 small-molecule kinase inhibitors (SMKIs) have been approved worldwide for treating various diseases, with nearly 70 FDA approvals specifically for cancer treatment, focusing on targets like the epidermal growth factor receptor (EGFR) family. Kinase-targeted strategies encompass monoclonal antibodies and their derivatives, such as nanobodies and peptides, along with innovative approaches like the use of kinase degraders and protein kinase interaction inhibitors, which have recently demonstrated clinical progress and potential in overcoming resistance. Nevertheless, kinase-targeted strategies encounter significant hurdles, including drug resistance, which greatly impacts the clinical benefits for cancer patients, as well as concerning toxicity when combined with immunotherapy, which restricts the full utilization of current treatment modalities. Despite these challenges, the development of kinase inhibitors remains highly promising. The extensively studied tyrosine kinase family has 70% of its targets in various stages of development, while 30% of the kinase family remains inadequately explored. Computational technologies play a vital role in accelerating the development of novel kinase inhibitors and repurposing existing drugs. Recent FDA-approved SMKIs underscore the importance of blood–brain barrier permeability for long-term patient benefits. This review provides a comprehensive summary of recent FDA-approved SMKIs based on their mechanisms of action and targets. We summarize the latest developments in potential new targets and explore emerging kinase inhibition strategies from a clinical perspective. Lastly, we outline current obstacles and future prospects in kinase inhibition.