Search Results (783)

Background: Epidermal growth factor receptor (EGFR) mutations are presented in approximately 50% of East Asian populations with advanced non-small cell lung cancer (NSCLC). While EGFR-tyrosine kinase inhibitors (TKIs) are the standard treatment, patient outcomes are also influenced by host-related factors. This study aimed to investigate clinical and radiological factors associated with early mortality and develop a prognostic prediction model in advanced EGFR-mutated NSCLC. Methods: A retrospective cohort was conducted in patients with EGFR-mutated NSCLC treated with first line EGFR-TKIs from January 2012 to October 2022 at Chiang Mai University Hospital. Clinical data and radiologic findings at the initiation of treatment were analyzed. A multivariable flexible parametric survival model was used to determine the predictors of death at 18 months. The predicted survival probabilities at 6, 12, and 18 months were estimated, and the model performance was evaluated. Results: Among 189 patients, 84 (44.4%) died within 18 months. Significant predictors of mortality included body mass index <18.5 or ≥23, bone metastasis, neutrophil-to-lymphocyte ratio ≥ 5, albumin-to-globulin ratio < 1, and mean pulmonary artery diameter ≥ 29 mm. The model demonstrated good performance (Harrell’s C-statistic = 0.72; 95% CI: 0.66–0.78). Based on bootstrap internal validation, the optimism-corrected Harrell’s C-statistic was 0.71 (95% CI: 0.71–0.71), derived from an apparent C-statistic of 0.75 (95% CI: 0.74–0.75) and an estimated optimism of 0.04 (95% CI: 0.03–0.04). Estimated 18-month survival ranged from 87.1% in those without risk factors to 2.1% in those with all predictors. A web-based tool was developed for clinical use. Conclusions: The prognostic model developed from fundamental clinical and radiologic parameters demonstrated promising utility in predicting 18-month mortality in patients with advanced EGFR-mutated NSCLC receiving first-line EGFR-TKI therapy. Full article

Background: Tyrosine kinase inhibitors (TKIs) have significantly improved outcomes in non-small cell lung cancer (NSCLC), especially among patients with actionable genetic mutations. However, the influence of family and personal medical history (FPMH) on clinical and treatment outcomes with TKI therapy remains underexplored. Methods: We conducted a retrospective cohort study involving 136 NSCLC patients receiving TKIs, categorized into two groups based on the presence or absence of documented FPMH. Clinical variables assessed included demographic data, comorbidities, Eastern Cooperative Oncology Group (ECOG) performance status, tumor characteristics, genetic mutations (EGFR, ALK, ROS1), treatment responses, toxicity profiles, and survival outcomes. Statistical analyses included Chi-square tests, t-tests, Mann–Whitney U tests, Spearman correlation, and univariate logistic regression (p < 0.05 threshold for significance). Results: Patients with FPMH (n = 34) had a significantly higher burden of chronic diseases (58.8% vs. 15.7%), poorer ECOG scores (≥3: 8.8% vs. 1.0%), increased recurrence (41.2% vs. 20.6%), and greater chemotherapy-related toxicity (50.0% vs. 28.4%) compared to those without FPMH (n = 102). However, there were no significant differences in survival duration or mutation status between the two groups. Conclusions: FPMH may be a predictive factor for treatment complications and recurrence in NSCLC patients receiving TKIs, although it does not appear to influence survival or genetic mutation status. These findings support the need for personalized clinical monitoring strategies based on medical history. Full article

Central nervous system metastases involving the brain parenchyma and leptomeninges are common in non-small cell lung cancer, especially cases with EGFR mutations. Here, we examine treatment options for EGFR-mutated non-small cell lung cancer patients with central nervous system metastases, highlighting the efficacy of third-generation EGFR-targeted tyrosine kinase inhibitors. Furthermore, we examine the interplay of this modality with chemotherapy or radiation in resistant cases. Full article

Background: This study aimed to develop a nomogram based on the most relevant clinical, CT, and radiomic features comprising 11 key signatures (2 clinical, 2 CT-based, and 7 radiomic) for the non-invasive prediction of the EGFR mutation status and to support the timely initiation of tyrosine kinase inhibitor (TKI) therapy in patients with non-small cell lung cancer (NSCLC) adenocarcinoma. Methods: Retrospective real-world data were collected from 521 patients with histologically confirmed NSCLC adenocarcinoma who underwent CT imaging and either surgical resection or pathological biopsy for EGFR mutation testing. Five Random Forest classification models were developed and trained on various datasets constructed by combining clinical, CT, and radiomic features extracted from CT image regions of interest (ROIs), with and without feature preselection. Results: The model trained exclusively on the most relevant clinical, CT, and radiomic features demonstrated superior predictive performance compared to the other models, with strong discrimination between EGFR-mutant and wild-type cases (AUC = 0.88; macro-average = 0.90; micro-average = 0.89; precision = 0.90; recall = 0.94; F1-score = 0.91; and accuracy = 0.87). Conclusions: A nomogram constructed using a Random Forest model trained solely on the most informative clinical, CT, and radiomic features outperformed alternative approaches in the non-invasive prediction of the EGFR mutation status, offering a promising decision-support tool for precision treatment planning in NSCLC. Full article

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide, with oral squamous cell carcinoma (OSCC) accounting for a significant portion of cases. Despite advancements in treatment, only modest gains have been made in HNSCC/OSCC control. Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have emerged as targeted therapies for OSCC in clinical trials. However, their clinical efficacy remains a challenge. Cannabidiol (CBD), a non-psychoactive phytochemical from cannabis, has demonstrated anticancer and immunomodulatory properties. CBD induces apoptosis and autophagy and modulates signaling pathways often dysregulated in HNSCC. This review summarizes the molecular mechanisms of EGFR-TKIs and CBD and their clinical insights and further discusses potential implications of combination targeted therapies. Full article

Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) is the major subtype, accounting for more than 85% of all lung cancer cases. Recent advances in precision oncology have allowed NSCLC patients bearing specific oncogenic epidermal growth factor receptor (EGFR) mutations to respond well to EGFR tyrosine kinase inhibitors (TKIs). Due to the high EGFR mutation frequency (up to more than 50%) observed particularly in Asian NSCLC patients, EGFR-TKIs have produced unprecedented clinical responses. Depending on their binding interactions with EGFRs, EGFR-TKIs are classified as reversible (first-generation: gefitinib and erlotinib) or irreversible inhibitors (second-generation: afatinib and dacomitinib; third-generation: osimertinib). While the discovery of osimertinib represents a breakthrough in the treatment of NSCLC, most patients eventually relapse and develop drug resistance. Novel strategies to overcome osimertinib resistance are urgently needed. In Asian countries, the concomitant use of Western medicine and traditional Chinese medicine (TCM) is very common. Ganoderma lucidum (Lingzhi) and Coriolus versicolor (Yunzhi) are popular TCMs that are widely consumed by cancer patients to enhance anticancer efficacy and alleviate the side effects associated with cancer therapy. The bioactive polysaccharides and triterpenes in these medicinal mushrooms are believed to contribute to their anticancer and immunomodulating effects. This review presents the latest update on the beneficial combination of Lingzhi/Yunzhi and EGFR-TKIs to overcome drug resistance. The effects of Lingzhi/Yunzhi on various oncogenic signaling pathways and anticancer immunity, as well as their potential to overcome EGFR-TKI resistance, are highlighted. The potential risk of herb–drug interactions could become critical when cancer patients take Lingzhi/Yunzhi as adjuvants during cancer therapy. The involvement of drug transporters and cytochrome P450 enzymes in these herb–drug interactions is summarized. Finally, we also discuss the opportunities and future prospects regarding the combined use of Lingzhi/Yunzhi and EGFR-TKIs in cancer patients. Full article

Background/Objectives: The fat mass and obesity-associated (FTO) protein demethylates nuclear N6-Methyladenosine (m6A) on mRNA, facilitates tumor growth, and contributes to therapeutic resistance in multiple cancer types. Recent evidence demonstrates several roles of FTO in tumorigenesis. In this study, we seek to explore the role of FTO in non-small cell lung cancer (NSCLC) tumorigenicity and its relationship with epidermal growth factor receptor (EGFR) tyrosine kinase resistance. Methods: We performed qPCR, immunoblotting, viability assays, migration assays, and ATP assays to investigate the functions of FTO in EGFR tyrosine kinase inhibitor (TKI) resistance, specifically to erlotinib, in three NSCLC cell lines harboring either wild-type or mutant EGFR. We also performed immunohistochemistry on lung tumor tissues from patients diagnosed at different stages of NSCLC. Results: Our study found an upregulation of FTO in erlotinib-resistant (ER) cell lines at both the gene and protein levels. FTO inhibition and knockdown significantly reduced cell viability of erlotinib-resistant H2170 and PC9 cells by over 30% when treated with 0.8 µM of Dac51 and about 20% when treated with siFTO. FTO inhibition also slowed down the migration of ER cells, and the effect was even more pronounced when combined with erlotinib. Furthermore, FTO was found to be overexpressed in late-stage NSCLC tumor tissues compared to early-stage tumors, and it was upregulated in patients who smoked. Conclusions: These findings suggest FTO might mediate resistance and tumor growth by augmenting cell proliferation. In addition, FTO can be a potential prognostic marker in NSCLC patients. Full article

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) significantly enhance the median survival of patients with lung adenocarcinoma (ADC) that harbor EGFR-sensitive mutations. However, most patients inevitably experience tumor relapse owing to drug resistance. We aimed to identify potential serum biomarkers for predicting post-EGFR-TKI treatment relapse in patients with advanced-stage lung ADC. Methods: Among 27 patients, including 6 and 21 with early and late relapse, respectively, differentially expressed proteins between patients with early and late relapses were identified using liquid chromatography and tandem mass spectrometry and subsequently validated using Western blotting. Predictive ability was assessed using the receiver operating characteristic curve and area under the curve (AUC) analysis. The association between the clinical variables and treatment response was evaluated using the chi-square test. Results: The serum expression levels of the translocated promoter region (TPR), junction plakoglobin (JUP), and fibrinogen alpha chain (FGA) were significantly higher in patients with late rather than early relapse. The findings indicated that TPR and FGA exhibited good diagnostic performance, with AUCs of 0.946 (p = 0.002; 95% confidence interval [CI], 0.84–1.05) and 0.809 (p = 0.034; 95% CI, 0.65–0.97), respectively. Conclusions: Our results suggest that the TPR and FGA levels are potential predictors of post-EGFR-TKI treatment relapse. Full article

Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown clinical activity for patients with EGFR-mutated non-small-cell lung cancer (NSCLC). However, the development of resistance to EGFR-TKIs is almost inevitable, posing a significant barrier to long-term survival. Local ablative therapy (LAT) may facilitate the prolonged survival of patients with oligometastatic NSCLC. Therapeutic combinations of EGFR-TKIs and LAT for residual disease have been suggested to be potentially effective in EGFR-mutated NSCLC with induced oligometastatic disease, wherein a few lesions remain following initial EGFR-TKI treatment. Various resistance pathways for third-generation EGFR-TKIs including osimertinib, current standard of care for patients with EGFR-mutated NSCLC, have also been identified. In addition to resistance mechanisms, the disease-progression pattern may be an essential element for achieving long-term response and survival. Oligo-progressive disease is a state in which only a few lesions become resistant, whereas many lesions remain controlled with effective systemic therapy. Previous studies have shown that LAT for all oligo-progressive lesions could provide survival benefits. This review discusses the current treatment options and potential future therapeutic developments for patients with EGFR-mutated NSCLC who have synchronous oligometastatic disease, oligo-residual disease during treatment with EGFR-TKIs, and oligo-progressive disease following resistance to EGFR-TKIs. Full article

Epidermal growth factor receptor (EGFR) mutations occur in approximately 10–20% of Caucasian and up to 50% of Asian patients with oncogene-addicted non-small cell lung cancer (NSCLC). Most frequently, alterations include exon 19 deletions and exon 21 L858R mutations, which confer sensitivity to EGFR tyrosine kinase inhibitors (TKIs). In the last decade, the third-generation EGFR-TKI osimertinib has represented the first-line standard of care for EGFR-mutant NSCLC. However, the development of acquired mechanisms of resistance significantly impacts long-term outcomes and represents a major therapeutic challenge. The mesenchymal–epithelial transition (MET) gene amplification and MET protein overexpression have emerged as prominent EGFR-independent (off-target) resistance mechanisms, detected in approximately 25% of osimertinib-resistant NSCLC. Noteworthy, variability in diagnostic thresholds, which differ between fluorescence in situ hybridization (FISH) and next-generation sequencing (NGS) platforms, complicates its interpretation and clinical applicability. To address MET-driven resistance, several therapeutic strategies have been explored, including MET-TKIs, antibody–drug conjugates (ADCs), and bispecific monoclonal antibodies, and dual EGFR/MET inhibition has emerged as the most promising strategy. In this context, the bispecific EGFR/MET antibody amivantamab has demonstrated encouraging efficacy, regardless of MET alterations. Furthermore, the combination of the ADC telisotuzumab vedotin and osimertinib has been associated with activity in EGFR-mutant, c-MET protein-overexpressing, osimertinib-resistant NSCLC. Of note, several novel agents and combinations are currently under clinical development. The success of these targeted approaches relies on tissue re-biopsy at progression and accurate molecular profiling. Yet, tumor heterogeneity and procedural limitations may challenge the feasibility of re-biopsy, making biomarker-agnostic strategies viable alternatives. Full article

Abnormal expressions and genetic mutations of EGFR are broadly involved in the progression of many human solid tumors, which has led to the development of small molecule inhibitors (TKIs). However, patients’ tumors usually develop resistance to targeted therapeutic TKIs after a period of treatment, mostly due to secondary mutations in EGFR. To date, three major and prevalent point mutations in EGFR, including L858R, T790M, and C797S, impact the use of TKIs in non-small cell lung cancer patients. Although at least four generations of TKIs have been designed and developed by targeting these mutations, how each mono, dual, or triple variant responds to clinical TKIs remains largely undeciphered. To fill this gap, we constructed a series of EGFR mutants and assessed their responses to clinical TKIs in vitro. The first-generation TKI, erlotinib, completely blocked the autophosphorylation of WT, L858R, C797S, and C797S/L858R, but only partially, if at all, in EGFR containing the T790M mutation alone or in combination. The third generation, osimertinib, completely abolished the autophosphorylation of WT, T790M, L858R, and T790M/L858R. It also significantly inhibited C797S and C790S/L858R, but had no effect on T790M/C797S or T790M/C797S/L858R. EAI045, as the fourth-generation TKI, almost completely inhibited WT and all mutants in complete growth media, but EGF-mediated phosphorylation of WT, C797S, and C797S/L858R were only partially inhibited in quiescence media, while the other mutants were fully inhibited. Furthermore, the abolishment of the enhanced tolerance to Dox in cells transiently expressing T790M/L858R and T790M/C797S/L858R by EAI045 suggests that their enhanced autophosphorylation is involved in their resistant ability. These findings provide some insights into how patients carrying typical mutations should be correctly and efficiently treated and why patients present side effects (because of non-specific inhibitory effects on cells without EGFR mutations). Full article

Background: Organic anion transporter 3 (OAT3) in the kidney proximal tubule cells plays a critical role in renal clearance of numerous endogenous metabolites and exogenous drugs and toxins. In this study, we discovered that epidermal growth factor (EGF) regulates the expression and activity of OAT3 through palmitoylation, a novel mechanism that has never been described in the OAT field. Methods/Results: Our results showed that treatment of OAT3-expressing cells with EGF led to a ~40% increase in OAT3 expression and OAT3-mediated transport of estrone sulfate, a prototypical substrate for OAT3. EGF-stimulated OAT3 transport activity was abrogated by H-89, a protein kinase A (PKA) inhibitor, indicating that an EGF-PKA signaling pathway is involved in the regulation of OAT3. We also showed that treatment of OAT3-expressing cells with EGF resulted in an enhancement of OAT3 palmitoylation, a novel type of post-translational modification for OATs, and such an enhancement was blocked by H-89, suggesting that the EGF-PKA signaling pathway participated in the modulation of OAT3 palmitoylation. Palmitoylation was catalyzed by a group of palmitoyltransfereases, and we showed that OAT3 palmitoylation and expression were inhibited by 2-BP, a general inhibitor for palmitoyltransfereases. We also explored the relationship among EGF/PKA signaling, OAT palmitoylation, and OAT transport activity. We treated OAT3-expressing cells with EGF or Bt2-cAMP, a PKA activator, in the presence and absence of 2-BP, followed by the measurement of OAT3-mediated transport of estrone sulfate. We showed that both EGF- and Bt2-cAMP-stimulated OAT3 transport activity were abolished by 2-BP, suggesting that palmitoylation mediates the regulation of EGF/PKA on OAT3. Finally, we showed that osimertinib, an anti-cancer drug/EGFR inhibitor, blocked EGF-stimulated OAT3 transport activity. Conclusions: In summary, we provided the first evidence that palmitoylation transduces the EGF/PKA signaling pathway to the modulation of OAT3 expression and function. Our study also provided an important implication that during comorbidity therapies, EGFR inhibitor drugs could potentially decrease the transport activity of renal OAT3, which would subsequently alter the therapeutic efficacy and toxicity of many co-medications that are OAT3 substrates. Full article

Non-small-cell lung cancer (NSCLC) can harbour different HER2 alterations: HER2 protein overexpression (2–35%), HER2 gene amplification (2–20%), and gene mutations (1–4%). The discovery of the HER2 gene in the 1980s raised great expectations for the treatment of several tumours. However, it was only in 2004 that HER2 mutations were identified, and they currently represent a key druggable target in NSCLC. Despite numerous strengths, there is only one FDA/EMA-approved targeted therapy, an antibody-drug conjugate (ADC) called trastuzumab deruxtecan for pretreated patients with HER2 mutant NSCLC. In the first-line treatment, the standard of care (SoC) remains chemotherapy with or without immunotherapy. In the past, pan-HER tyrosine kinase inhibitors (TKIs) were extensively studied with poor results. But, two newly developed HER2-specific TKIs with low EGFR WT inhibition (BAY2927088 and zongertinib) reported encouraging results and received the breakthrough therapy designation from the FDA. Ongoing clinical trials are investigating new agents. This review focuses on HER2 alterations. Additionally, the anti-HER2 therapies explored so far will be discussed in detail, including the following: HER2 inhibitors (pan-inhibitors and selective inhibitors), monoclonal antibodies (mAbs), and ADCs. A section of this paper is dedicated to the role of immunotherapy in HER2-altered NSCLC. The last section of this paper focuses on the drugs under development and their challenges. Full article

The current treatment for refractory BRAF-V600E mutant metastatic colorectal cancer (mCRC) involves combined inhibition of BRAF and the epidermal growth factor receptor (EGFR). However, tumour responses are often short-lived due to a rebound in mitogen-activated protein kinase (MAPK) activity. In this study, we combined short-term cell viability assays with long-term regrowth assays following drug removal over a period of three weeks. This allowed assessment of regrowth after therapy discontinuation. We tested the effect of combined BRAF inhibition (encorafenib) and EGFR inhibition (afatinib) on BRAF-V600E mutant CRC patient-derived organoids (PDOs). Combined EGFR/BRAF inhibition initially caused a major reduction in PDO growth capacity in BRAF-V600E mutant PDOs. This was followed by rapid regrowth after drug removal, mirroring clinical outcomes. EGFR inhibition in BRAF-V600E mutant PDOs led to activation of the insulin receptor (IR) and insulin-like growth factor-1 receptor (IGF1R). The IGF1R/IR inhibitor linsitinib prevented the rebound in MAPK activity following removal of afatinib and encorafenib, prevented regrowth of CRC PDOs, and improved the anti-tumour response in an in vivo model. PDO regrowth assays allow the identification of pathways driving tumour recurrence. IR/IGF1R-inhibition prevents regrowth following golden standard MAPK pathway-targeted therapy and provides a strategy to improve the treatment of BRAF-V600E mutant CRC Full article

Epithelial differentiation and function are tightly coupled to the keratin intermediate filament cytoskeleton. Keratin filaments are unique among the cytoskeletal filament systems in terms of biochemical properties, diversity and turnover mechanisms supporting epithelial plasticity in response to a multitude of environmental cues. Epidermal growth factor (EGF) is such a cue. It is not only intricately intertwined with epithelial physiology but also modulates keratin filament network organization by increasing keratin filament turnover. The involved EGF receptor (EGFR)-dependent intracellular signaling cascades, however, have not been identified to date. We therefore tested the effect of selective inhibitors of downstream effectors of the EGFR on keratin filament turnover using quantitative fluorescence recovery after photobleaching experiments as readouts. We find that SRC and ERK kinases are involved in the regulation of keratin filament turnover, whereas PI3K/AKT and FAK have little or no effect. The identification of SRC and ERK as major keratin filament regulators extends beyond EGF signaling since they are also activated by other signals and stresses. Our data unveil a mechanism that allows modification of the properties of keratin filaments at very high temporal and spatial acuity. Full article