Search Results (624)

Breast cancer and lung adenocarcinoma share common features, including female predominance and the expression of estrogen receptor (ER) and epidermal growth factor receptor (EGFR) during carcinogenesis. Patients with breast cancer have a significantly higher risk of developing second primary lung cancer than those without breast cancer. ER beta expression is associated with resistance to EGFR tyrosine kinase inhibitors (TKIs) in EGFR-mutant lung adenocarcinoma, indicating a potentially important interaction between ER and EGFR. However, the mechanisms underlying this crosstalk remain poorly understood. Our clinical data showed a significant correlation between antiestrogen treatment for breast cancer and mutant EGFR expression (p = 0.021) in lung adenocarcinoma patients. In vitro, tamoxifen upregulated phosphorylated EGFR (p-EGFR) in EGFR-mutant lung adenocarcinoma cell lines. Heparin-binding EGF-like growth factor was identified as a key mediator from the ER pathway that stimulates p-EGFR. Tamoxifen counteracts estrogen’s effect and restores p-EGFR upregulation. Furthermore, coadministration of tamoxifen and the EGFR TKI gefitinib potentially inhibited p-EGFR expression in EGFR-mutant lung adenocarcinoma. Regular follow-up with chest computed tomography is recommended for patients with breast cancer. For those diagnosed with both ER-positive breast cancer and EGFR-mutant lung adenocarcinoma, combined tamoxifen and EGFR TKI therapy may offer an effective targeted treatment strategy. Full article

Background: Osimertinib is a third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) with high efficacy in treating patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR-activating mutations. Although osimertinib is a frontline anticancer agent for NSCLC, several patients inevitably develop tumor recurrence caused by osimertinib resistance. The activation of anexelekto (AXL) or fibroblast growth factor receptor 1 (FGFR1) is reported as a major factor driving osimertinib resistance in NSCLC. Thus, targeting AXL and FGFR1 offers the potential to overcome osimertinib resistance. Methods: In this study, we generated osimertinib-resistant cell lines from EGFR-mutant NSCLC cell lines in vitro and investigated the biological significance of AX-0085 on these cell lines by conducting transcriptomic analyses. Results: The expression of several genes associated with MAPK, ERK, and FGF receptor signaling pathways, including AXL, was altered upon AX-0085 treatment of osimertinib-resistant cells. Furthermore, AX-0085 treatment effectively blocked AXL and FGFR1 activation and sensitized osimertinib-resistant cells. Additionally, AX-0085 inhibited AXL and FGFR1-dependent oncogenic events, including cell proliferation, clonogenicity, and migration. Conclusions: The dual inhibition of AXL and FGFR1 by AX-0085 can overcome acquired osimertinib resistance, supporting its potential as a therapeutic strategy for treating patients with osimertinib-resistant tumors. Full article

Background/Objectives: Signaling imbalances involving epidermal growth factor receptor (EGFR) and aldose reductase (ALR2) are frequently associated with the biology of several solid tumors, including non-small-cell lung cancer (NSCLC) and breast cancer. This work sought to prepare and investigate a small set of hydrazonylthiazole derivatives as potential modulators of both targets with relevance to cancer therapy. Methods: Thirteen compounds (1–13) were synthesized and examined for their effects on A549 (NSCLC), MCF-7 (breast cancer), and Jurkat leukemia cells, together with peripheral blood mononuclear cells (PBMCs) to determine selectivity. The most active molecules were further analyzed through apoptosis studies, EGFR and ALR2 inhibition assays, docking calculations, and 200 ns molecular dynamics (MD) simulations. SwissADME was used to estimate pharmacokinetic and drug-likeness features. Results: Among all derivatives, compound 13, prepared here for the first time, showed the strongest activity on A549 and MCF-7 cells (IC₅₀: 1.33 ± 0.41 µM; 1.74 ± 0.38 µM) and displayed a very high selectivity index (SI = 138.9). It also triggered apoptosis in A549 cells and reduced EGFR activity by 74% at 10 µM. In contrast, compound 5 acted as the most efficient ALR2 blocker (K_I = 0.08 ± 0.01 µM). MD simulations showed that both compounds maintained stable contact patterns with essential residues in the EGFR and ALR2 binding pockets. SwissADME analysis suggested suitable oral absorption and drug-likeness for both molecules. Conclusions: Compound 13 behaves as a selective EGFR-directed agent capable of inducing apoptotic cell death in NSCLC, while compound 5 shows strong affinity toward ALR2. These outcomes indicate that both structures may serve as useful starting points for further development of small molecules acting on EGFR- and ALR2-related pathways. Full article

HER2 (human epidermal growth factor receptor 2) is a receptor tyrosine kinase which is overexpressed in ~20% of patients with oesophagogastric adenocarcinoma (EGA). HER2 represents a targetable transmembrane glycoprotein receptor of the epidermal growth factor receptor (EGFR) family, which plays a crucial role in cell proliferation, survival, and differentiation. HER2 significantly influences the tumour microenvironment (TME) through various mechanisms, creating a niche that supports tumour progression, immune evasion, and therapeutic resistance. In HER2-positive EGA, aberrant signalling pathways, such as PI3K/AKT and MAPK/ERK, enhance tumour cell survival and proliferation, whilst upregulation of angiogenic factors like VEGF fosters vascularization, meeting a tumour’s metabolic demands and facilitating its proliferation. HER2 also modulates the tumour immune microenvironment (TIME) by downregulating MHC molecules and recruiting immunosuppressive cells, including regulatory T-cells (T-reg) and tumour-associated macrophages (TAMs), which release cytokines that further inhibit anti-tumour immune responses. Together, these factors foster a pro-inflammatory, immunosuppressive microenvironment that underpins resistance to HER2-targeted therapies. As more HER2-directed treatments become available, such as trastuzumab–deruxtecan (T-DXd), gaining a deeper understanding of the multifaceted influence of HER2 on the TME in EGA will be crucial for the development of improved targeted treatments that can overcome these challenges and lead to advancements in targeted treatment for HER2-overexpressing EGA. This review provides a comprehensive overview of the impact of HER2 on the TME in EGA and highlights the challenge it represents as well as the opportunity for novel therapeutic development and the implications for patients in terms of clinicopathological outcomes. Full article

Human Epidermal Growth Factor Receptor 2 (HER2)-positive breast cancer is an aggressive malignancy with limited treatment options. The herbal composition SLC contains Salvia miltiorrhiza Bunge (Dan shen), Ligusticum wallichii Franch. (Chuan xiong), and Carthamus tinctorius L. (Hong hua), three herbs that have demonstrated antitumor properties. This study aims to investigate the inhibitory effects and mechanisms of SLC against HER2-positive breast cancer. UPLC-Q/TOF-MS identified 113 compounds in SLC. SLC inhibited the proliferation, migration, and mitochondrial function of HER2-positive cells by reducing glucose uptake, ATP production, and oxygen consumption rate (OCR). Furthermore, SLC downregulated the levels of p-HER2/HER2, p-AKT/AKT, and p-ERK/ERK by Western blot, thereby inhibiting the HER2 signaling pathway. Mechanistically, SLC decreased the protein expression of PDK1 and inhibited the phosphorylation of PDHA1 (Ser293), and also inhibited mitochondrial-related proteins in SIRT1/PGC-1α/NRF1/TFAM signaling axes. Additionally, through the overexpression of PDK1, SLC repressed PDK1, downregulated PDHA1, and induced apoptosis. In vivo xenograft model studies demonstrated that SLC inhibited tumor growth. Molecular docking highlighted Monomethyl lithospermate as a key active component. Overall, SLC influences oxidative phosphorylation via the PDK1/PDHA1 and SIRT1/PGC-1α/NRF1/TFAM signaling pathways and downregulates the HER2 pathway, thereby ultimately inhibiting HER2-positive breast cancer progression. Full article

Background: Tyrosine kinase inhibitors (TKIs) are crucial to treating endocrine-related malignancies, including advanced thyroid cancers and neuroendocrine tumors, but their benefit is tempered by cutaneous adverse events (CAEs) that impair adherence and quality of life. Objective: To summarize the dermatologic toxicities of TKIs used in endocrine oncology and provide practical, multidisciplinary guidance for prevention and management. Methods: Narrative synthesis of clinical trial reports, post-marketing studies, and specialty guidelines pertinent to lenvatinib, vandetanib, cabozantinib, and other commonly used TKIs, integrating dermatologic and endocrine perspectives on mechanisms and care pathways. Results: VEGFR-targeted TKIs frequently cause hand–foot skin reaction, xerosis, fissuring, paronychia, and impaired wound healing; multikinase inhibition also produces alopecia, pigmentary changes, and mucositis. Epidermal growth factor receptor (EGFR) and rearranged during transfection (RET) inhibition with vandetanib is associated with acneiform eruption, photosensitivity, and nail fragility. Pathogenesis reflects on-target inhibition of VEGF/EGFR signaling leading to keratinocyte dysfunction, vascular fragility, and altered eccrine mechanics. Early risk stratification, patient education, and bundle-based prophylaxis (emollients, keratolytics, urea-based creams, sun protection) reduce incidence and severity. Grade-based algorithms combining topical corticosteroids/antibiotics, dose interruptions or reductions, and short systemic courses (e.g., doxycycline, antihistamines) enable symptom control while maintaining anticancer intensity. Close coordination around procedures minimizes wound-healing complications. Conclusions: Dermatologic toxicities are predictable, mechanism-linked, and manageable with proactive, multidisciplinary care. Standardized prevention and treatment pathways tailored to specific TKIs—particularly lenvatinib, vandetanib, and cabozantinib—can preserve dose intensity, optimize quality of life, and sustain antineoplastic efficacy. Full article

Background/Objectives: Chronic synovitis is a hallmark of osteoarthritis (OA) progression, driving cartilage degradation via inflammatory mediators. While the MAPK signaling pathway is implicated in OA pathogenesis its activation patterns in hip synovium remain poorly characterized, and regional differences within the synovial membrane have not been systematically examined. This research aims to determine the expression of extracellular signal-regulated kinase 1/2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK), c-Jun N-terminal kinase (JNK), and the Epidermal Growth Factor Receptor (EGFR) in the MAPK signaling pathway in the synovial membrane of osteoarthritic hips. Methods: We compared synovial immunofluorescence expression of the aforementioned proteins in a control (CTRL) group of subjects with femoral neck fractures and a group with hip OA. Results: Higher ERK1/2 immunoexpression was detected in the intima compared with the subintima in the CTRL group (p < 0.05), and a similar distribution was observed in the OA group (p < 0.0001). The intima of the OA group exhibited a considerably greater area percentage of positive signal than the intima of the CTRL group (p < 0.01). In all groups examined, we observed that p38 MAPK expression was markedly more positive in the intima than in the subintima (p < 0.0001), but without statistically significant differences between groups. JNK and EGFR immunoexpression were higher in the intima than in the subintima across all analyzed groups, but the difference did not reach statistical significance (p > 0.05). No differences in the expression of these two markers were detected between the CTRL and OA groups (p > 0.05). Differential analysis of the GEO dataset revealed no significant differences in expression between the OA and CTRL groups in the expression of MAPK1, MAPK3, MAPK8, MAPK9, MAPK10, and MAPK11. EGFR was significantly elevated in OA compared to CTRLs in the differential analysis of the GEO dataset. Conclusions: This study provides the first comprehensive analysis of MAPK pathway activation in hip OA synovium, revealing ERK1/2 as a key player with region-specific upregulation in the synovial intima. Combined with elevated EGFR expression, these findings suggest potential therapeutic targets for hip OA synovitis. The discordance between protein and mRNA levels for ERK1/2 indicates post-transcriptional regulation, warranting further investigation into phosphorylation status and functional activation. Our results support the development of targeted interventions for hip OA, a condition with limited treatment options beyond joint replacement. Full article

Oral and oropharyngeal squamous cell carcinomas (OSCC and OPSCC), two major sub-types of Head and Neck cancer, remain associated with significant morbidity and exhibit poor prognosis, with limited response to conventional therapies in advanced stages. Recent therapeutic strategies have increasingly focused on molecular targets involved in tumor proliferation, angiogenesis, and immune evasion. This overview provides a concise synthesis of targeted therapies under investigation or already in clinical use, including monoclonal antibodies against epidermal growth factor receptor (EGFR) (e.g., cetuximab) and immune checkpoint inhibitors (e.g., nivolumab, pembrolizumab), as well as inhibitors of programmed cell death protein 1 (PD-1) and its ligand (PD-L1) or agents targeting angiogenic and intracellular signaling pathways such as VEGF and mTOR. Alongside these novel agents, growing interest surrounds the repurposing of established pharmacological agents which appear to modulate tumor-related inflammation, metabolic dysregulation, and epithelial-to-mesenchymal transition. Metformin and statins, for instance, have demonstrated anti-proliferative and pro-apoptotic effects in preclinical OSCC models. Notably, recent evidence suggests that regular use of nonsteroidal anti-inflammatory drugs (NSAIDs), including aspirin, may improve survival specifically in patients with PIK3CA-altered Head and Neck tumors, potentially through modulation of the COX-2/PGE2 axis. Although prospective evidence remains limited and somewhat heterogeneous, existing preclinical and observational studies suggest that these agents may improve survival and reduce treatment-related toxicity, further pointing to the relevance of molecular stratification in guiding future repurposing strategies. This article aims to map the current therapeutic landscape, highlighting both established molecular targets and emerging repositioned drugs in the management of OSCC and OPSCC. Full article

The regenerative potential of the mammalian retina is limited, yet identifying signaling pathways that influence progenitor cell behavior remains an important step toward understanding the mechanisms of retinal development and plasticity. Epidermal Growth Factor Receptor (EGFR) signaling has been implicated in regulating proliferation and differentiation in the central nervous system, but its role in the postnatal retina is less defined. In this study, we employed an ex vivo explant model of the postnatal mouse retina to investigate the effects of sustained Epidermal Growth Factor (EGF) stimulation. Our results demonstrate that EGF extends the proliferative activity of progenitors that are normally quiescent after birth. However, the sustained EGFR activation (10 ng/mL, for 7 days) in the postnatal retina not only promotes EGFR+ progenitor proliferation but also maintains co-expression of Otx2 and Chx10, revealing a distinct progenitor population, suggesting that extended EGF signaling influences lineage allocation. These findings indicate that EGFR activation can modulate both the maintenance and differentiation potential of retinal progenitors in a context-dependent manner. While additional studies are needed to determine whether these progenitors develop into mature, functional neurons, our work provides a framework for future investigations into signaling pathways that may be leveraged to influence retinal development and plasticity. Full article

Mammalian sperm cells must undergo several processes collectively called capacitation before carrying out the acrosome reaction (AR), which is required for sperm penetration into the oocyte. The spontaneous acrosomal reaction (SAR), which can occur before the sperm cell reaches the vicinity of the oocyte, impairs the fertilizing ability of the sperm. This study examined the role of the Fer tyrosine kinase in sperm fertilizing activity. Inhibition of the Fer activity led to a 75% reduction in IVF rates in mice, indicating a critical role for Fer in fertilization. Further investigation of Fer’s role during sperm capacitation focused on its potential interaction with the epidermal growth factor receptor (EGFR). Inhibition of Fer during capacitation significantly decreased the EGFR activation state and increased the incidence of SAR, whereas inhibition of Fer during the acrosome reaction step had no effect on the EGF-induced AR. The effects of Fer inhibition on EGFR activation and SAR enhancement are mediated by the Ca²⁺ channel, CatSper. Notably, reduction in Ca²⁺ influx by CatSper inhibition revealed a significant increase in Fer phosphorylation/activation, while increasing intracellular Ca²⁺ concentrations completely inhibited this effect. Additionally, we show that Fer activation depends on a signaling cascade involving protein kinase A (PKA) that leads to EGFR activation through the following pathway: HCO₃⁻ → SAC → cAMP → PKA → Src → Fer → EGFR. Collectively, we decipher in this work a new regulatory cascade that leads to the Fer-directed activation of EGFR in sperm capacitation. Full article

Background/Objectives: Ovarian cancer remains one of the most lethal gynecologic malignancies, primarily due to late diagnosis and the development of chemoresistance. Adriamycin (ADR) is effective but limited by systemic toxicity. Natural bioflavonoids such as hesperidin (Hes) may enhance chemotherapy efficacy through oxidative, apoptotic, and immune modulation. This study investigated the antiproliferative, pro-apoptotic, and immunomodulatory effects of Hes and ADR in human ovarian adenocarcinoma cells (SKOV3), focusing on Forkhead box P3 (FOXP3) and epidermal growth factor receptor (EGFR) signaling pathways. Methods: SKOV3 were treated with increasing concentrations of Hes (10–400 µM) and ADR (0.01–0.4 µM), either individually or in combination at their half-maximal inhibitory concentration (IC₅₀) ratios. Cell viability (MTT assay), gene expression (qRT-PCR), cytokine levels (ELISA), and total antioxidant capacity (TAC) were assessed to evaluate treatment responses. Results: Both agents reduced cell viability in a dose- and time-dependent manner, with the combination exhibiting synergistic cytotoxicity after 48 h. Co-treatment markedly upregulated Caspase-3 and Bax while downregulating FOXP3 and EGFR. Antioxidant capacity was significantly enhanced in the Hes-treated and combination groups (p < 0.001). Conclusions: Hes and ADR synergistically suppressed proliferation, induced apoptosis, and modulated cytokine balance by inhibiting FOXP3- and EGFR-mediated oncogenic signaling. This combination demonstrates strong potential as an adjuvant therapeutic strategy for ovarian cancer. Full article

Triple-negative breast cancer (TNBC) remains a leading cause of cancer-related mortality in women, characterized by its aggressive nature and limited therapeutic options. TNBC is defined by the absence of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) expression, which excludes patients from targeted endocrine and HER2-directed therapies, contributing to poor prognosis. This study investigates BKS-112, a potent histone deacetylase 6 (HDAC6) inhibitor, for its anticancer activity against TNBC using MDA-MB-231 cells. We assessed HDAC protein expression and their prognostic implications, alongside in vitro experiments analyzing cell viability, apoptosis, autophagy, and colony formation. BKS-112 exhibited dose- and time-dependent reductions in cell viability, significant morphological alterations, and decreased colony formation. The compound increased the acetylation of histones H3, H4, and α-tubulin while downregulating HDAC6 expression and activity. Additionally, BKS-112 reduced cell migration, demonstrating anti-metastatic potential. It induced G1 phase cell cycle arrest and modulated key regulators, including cyclins and cyclin-dependent kinases (CDKs). Apoptosis was promoted through mitochondrial pathways, evidenced by changes in Bcl-2, Bax, and caspase activation. BKS-112 also elevated reactive oxygen species (ROS) levels, affecting apoptosis-related PI3K/AKT signaling. Autophagy was triggered by upregulating LC3 and Atg-7 expression. Collectively, these findings suggest that BKS-112 exerts robust anticancer effects by inducing cell cycle arrest, apoptosis, and autophagy, highlighting its therapeutic promise for TNBC treatment. Full article

Background and Objectives: Erlotinib, a tyrosine kinase inhibitor (TKI), is an established therapy for patients with metastatic non-small cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) mutations. Preclinical and clinical evidence suggests that chronic stress, mediated through β-adrenergic signaling, promotes tumor progression, angiogenesis, and therapy resistance. Furthermore, interactions between β-adrenergic signaling and EGFR pathways have been hypothesized to negatively influence treatment responses. Based on this rationale, we investigated whether concomitant beta-blocker use may improve survival outcomes in EGFR-mutant NSCLC patients treated with erlotinib. Materials and Methods: This retrospective analysis included 103 patients with metastatic EGFR-mutant NSCLC who received erlotinib. Patients were classified according to concurrent beta-blocker use, defined as continuous therapy for at least six months prior to erlotinib initiation, prescribed for cardiovascular indications. Progression-free survival (PFS) and overall survival (OS) were compared between beta-blocker users and non-users. Results: Patients receiving erlotinib with concomitant beta-blocker therapy achieved a median PFS (mPFS) of 21.4 months (95% CI, 13.1–29.7), compared with 9.7 months (95% CI, 6.7–12.7) in non-users (p = 0.003). Median OS (mOS) was 32.4 months (95% CI, 14.8–50.0) in the beta-blocker group versus 19.9 months (95% CI, 14.8–25.0) in the non-beta-blocker group (p = 0.010). Multivariate Cox regression confirmed beta-blocker use as an independent prognostic factor for both PFS (p = 0.004) and OS (p = 0.014). Conclusions: Concomitant beta-blocker use was associated with significantly prolonged survival in patients with EGFR-mutant metastatic NSCLC receiving erlotinib. These findings support the hypothesis that β-adrenergic inhibition enhances the efficacy of EGFR-targeted therapy. Prospective studies are warranted to validate these results and to further elucidate the underlying biological mechanisms. Full article

Lung cancer is a leading cause of cancer mortality worldwide. Targeted therapies with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) represent a significant advance in the management of lung cancer. However, their long-term efficacy is often limited by acquired resistance, particularly due to the T790M mutation, highlighting the need for novel EGFR-TKIs. Although compounds derived from Centella asiatica have demonstrated anticancer potential, their role in EGFR inhibition has not yet been reported. In this study, we investigated the inhibitory activity of two primary constituents, asiaticoside and asiatic acid, against wild-type and double-mutant (L858R/T790M) EGFR, as well as the anticancer effects of the more potent compound in lung cancer cells. A kinase activity assay revealed that asiatic acid potently inhibited both wild-type and double-mutant EGFR, whereas asiaticoside showed minimal inhibitory activity. Molecular docking demonstrated that asiatic acid bound to the ATP-binding pocket of both EGFR forms with binding energies superior to those of erlotinib and osimertinib. Treatment with asiatic acid significantly (i) reduced viability of A549 and H1975 cells while remaining non-toxic to BEAS-2B normal lung cells, (ii) enhanced cancer cell apoptosis, (iii) suppressed extracellular signal-regulated kinase (ERK) and protein kinase B (Akt) signaling pathways, and (iv) inhibited EGFR activation in A549 and H1975 cells. These results suggest that asiatic acid is a promising lead compound for anticancer drug development. Full article

Colorectal cancer (CRC) remains a major contributor to global cancer-related mortality, with rising incidence observed in several regions, including Saudi Arabia. This review compiles and critically analyzes recent preclinical research from Saudi-based institutions that investigates the anti-CRC potential of natural and synthetic compounds. Numerous natural products such as Nigella sativa, Moringa oleifera, Curcuma longa, and marine-derived metabolites have demonstrated cytotoxic effects through pathways involving apoptosis induction, reactive oxygen species (ROS) generation, and inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and cyclooxygenase-2 (COX-2). In parallel, synthetic and semi-synthetic agents, including C4–G4 (semi-synthetic hybrids designed from flavonoids and benzoxazole scaffolds that act as dual epidermal growth factor receptor (EGFR)/COX-2 inhibitors)), oxazole derivatives, and camptothecin-based nanocarriers, exhibit promising anti-tumor activity via molecular targeting of cyclin-dependent kinase 8 (CDK8), phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt), and β-catenin pathways. Selected in vivo studies primarily utilizing xenograft and chemically induced rodent models have shown reductions in tumor volume and modulation of apoptotic and inflammatory biomarkers. Additionally, green-synthesized metallic nanoparticles (NPs) and polyethylene glycol (PEG)-modified carriers have been investigated to improve bioavailability and tumor targeting of lead compounds. While these findings are encouraging, the majority remain in preclinical phases. Limitations such as poor solubility, lack of pharmacokinetic data, and absence of clinical trials impede translational progress. This review highlights the need for standardized evaluation protocols, mechanistic validation, and region-specific clinical studies to assess efficacy and safety. Given Saudi Arabia’s rich biodiversity and growing research capacity under national strategies like Vision 2030, the country is well-positioned to contribute meaningfully to CRC drug discovery. By integrating bioactive natural products, rationally designed synthetics, and advanced delivery platforms, a pipeline of innovative CRC therapeutics tailored to local and global contexts may be realized. Full article