Search Results (251)

Background: Anaplastic Lymphoma Kinase (ALK) is an oncogenic receptor tyrosine kinase implicated in several cancers. Despite the clinical success of ALK inhibitors, acquired resistance continues to drive the search for novel chemotypes. We developed a multiclass machine learning framework to classify ALK inhibitory activity using a curated ChEMBL dataset. Methods: Models were built using 2D molecular descriptors together with MACCS and ECFP4 fingerprints. Three widely used algorithms, Support Vector Machine (SVM), Random Forest (RF), and XGBoost, were applied for model development. Results: RF and XGBoost models demonstrated the best performance, achieving accuracies of ~0.75–0.79 with consistently high ROC–AUC values, particularly for fingerprint-based features. Bemis–Murcko scaffold analysis identified enriched chemotypes and underexplored scaffolds for further prioritization. The validated models were subsequently used to screen the Maybridge library, and compounds predicted to possess potential ALK inhibitory activity were prioritized for further computational evaluation. Applicability-domain filtering confirmed that the selected compounds occupied the predicted ALK inhibitor chemical space across multiple activity classes. The shortlisted compounds were subsequently evaluated by molecular docking to characterize their binding modes and interactions. Three candidate hits (SCR00078, SCR00073, and AW01085) were selected for further evaluation using 500 ns molecular dynamics simulations alongside the reference inhibitor Brigatinib. Simulation analyses revealed stable protein–ligand complexes and reduced conformational fluctuations relative to apo ALK, while MM/PBSA calculations identified SCR00078 and AW01085 as the most favorable binders. Conclusions: This integrated ML-to-simulation workflow prioritizes structurally novel candidate hits with predicted ALK inhibitory activity and provides an effective strategy for scaffold discovery and hit prioritization. Full article

The review covers research on dual-target antitumor agents over the past five years. One of the targets is histone deacetylases (HDACs), while the second potential target is a protein group located both on the membrane surface (phosphatidylinositol 3-kinase (PI3K), anaplastic lymphoma kinase (ALK), receptor tyrosine kinase (AXL), tyrosine protein kinase (HER2), FMS-like tyrosine kinase (FLT3), and vascular endothelial growth factor receptor (VEGFR2)) and in the nucleus (serine/threonine protein kinase Wee1, DNA methyltransferase (DNMT), dual-specificity phosphatase (CDC25A), an enzyme from the cyclin-dependent kinase family (CDK9), dual-specificity tyrosine-serine/threonine kinase (DYRK2), and BET family proteins (BRD4, BD1, and BD2)). This review presents the results of studies on the inhibitory activity of various HDAC isoforms and other enzymes, as well as in vitro cytotoxicity studies on both neoplastic and healthy cells. It also includes selectivity studies, in vivo experiments (changes in tumor volume in mice) and oral bioavailability assessments. The review also describes the chemical structures of several dual-target agents and identifies the molecular fragments responsible for inhibiting different targets. Based on the studies reviewed in this paper, it can be concluded that some dual inhibitors have superior in vitro cytotoxicity and exhibit selectivity towards some tumor cells compared to monofunctional reference compounds. These findings may be useful for molecular design in the field of polypharmacology, with the aim of developing new dual-target molecules that exhibit improved antitumor activity and selectivity towards neoplastic cells. Full article

Introduction: Chronic lymphedema (CL) can lead to infectious complications, skin inflammation, and tumors. Consequently, patients with CL are at increased risk of developing several malignant cutaneous neoplasms, including Kaposi sarcoma, B-cell lymphoma, and angiosarcoma. T-cell lymphomas are rarely associated with CL. Additionally, systemic anaplastic large cell lymphomas (ALCLs) are usually positive for anaplastic lymphoma kinase (ALK). We present the case of a 73-year-old patient who exhibited angiomatous-appearing cutaneous lesions, ultimately leading to a diagnosis of ALK-negative systemic ALCL, exclusively localized to the CL of the left lower limb. Case Report: A 73-year-old man presented with a 12-year history of CL affecting his left lower limb. He subsequently developed, over a three-month period, an angiomatous-like plaque accompanied by multiple nodules on the same limb. Physical examination showed widespread lymphadenopathy. A skin and lymph node biopsy specimen displayed CD3+, CD30+, ALK-negative atypical lymphoid infiltrates consistent with ALK-negative systemic ALCL with secondary cutaneous involvement. A total body computed tomography (CT) scan showed hepatosplenomegaly and generalized lymphadenopathy. In the Department of Hematology, combination chemotherapy of cyclophosphamide, Adriamycin, vincristine, and prednisolone (CHOP) was started, but the patient was lost to follow-up. Conclusions: We report a unique case of ALK-negative systemic ALCL in a 73-year-old man who presented with angiomatous-like nodular lesions occurring at the site of chronic limb lymphedema. This case demonstrates the importance of a systemic evaluation of all CD30-positive cutaneous lymphoid infiltrates and suggests that chronic lymphatic stasis may be a predisposing factor in the development of ALCL. Full article

Background/Objectives: Anaplastic lymphoma kinase (ALK) fusion is a driver gene translocation detected in 3–5% of patients with non-small-cell lung cancer (NSCLC). Next-generation sequencing (NGS)-based tests are the standard of care for detecting actionable gene alterations; however, false negatives remain a concern. Immunohistochemical staining is another reliable, rapid, and low-cost method for detecting ALK fusions. Previous studies have reported high concordance with NGS, although further studies are needed to draw definitive conclusions. Methods: A retrospective analysis was conducted on consecutive patients with NSCLC who were tested using the Oncomine Dx Target Test (ODxTT), an amplicon-based DNA and RNA NGS test for NSCLC, and ALK-immunohistochemistry (IHC) at our institution between 8 August 2019 and 11 April 2025. Results: Of 919 eligible patients included in this study, ALK fusion was detected in 30 (3.26%) patients, whereas ALK-IHC was positive in 35 (3.80%) patients. The concordance and κ coefficient of the two tests were 99.4% and 0.920, respectively. The sensitivity, specificity, positive predictive value, and negative predictive value of ALK-IHC for ODxTT were 100%, 99.4%, 85.7%, and 100%, respectively. Five discordant patients were NGS negative and IHC positive. Among the five discordant cases, one had a false-negative NGS result, whereas the remaining four had false-positive ALK-IHC results, including three patients with neuroendocrine carcinomas. Conclusions: ALK-IHC shows diagnostic accuracy comparable to ODxTT, although prudent interpretation is needed for patients without adenocarcinoma. Our findings suggest the complementary role of ALK-IHC alongside NGS-based testing, particularly in patients with a high pre-test probability of harbouring ALK fusions. Full article

In the era of precision medicine, managing non-small cell lung cancer (NSCLC) requires pathological confirmation, accurate nodal staging, and comprehensive biomarker profiling performed rapidly and concurrently. In the 9th edition of the TNM classification, the N2 category is subdivided into single-station (N2a) and multistation (N2b) subcategories, highlighting the clinical importance of precise mediastinal staging. This refinement necessitates systematic nodal evaluation using minimally invasive modalities such as endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) and endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) to appropriately stratify patients for surgery, neoadjuvant therapy, and definitive chemoradiotherapy. Concurrently, although N1 has not been formally subclassified because of the lack of standardized clinical diagnostic criteria, the increasing use of sublobar resection for early-stage NSCLC requires more precise hilar and intrapulmonary nodal assessments, which can potentially be facilitated by emerging technologies such as thin convex-probe EBUS. Concurrently, adequate tissue acquisition is essential for timely biomarker testing. Before administering neoadjuvant immune checkpoint inhibitors, actionable driver alterations, such as epidermal growth factor receptor (EGFR) mutations and anaplastic lymphoma kinase (ALK) rearrangements, must be identified to select appropriate treatment and prevent severe sequential toxicities associated with subsequent targeted therapies. This review highlights the indispensable role of endoscopic nodal staging and multidisciplinary collaboration in adapting to the updated TNM classification and optimizing personalized treatment strategies for patients with NSCLC. Full article

Aim: Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal neoplasm with few reported mandibular cases. This review aims to describe the clinical characteristics, surgical management and outcomes of 13 mandibular IMT cases, and to introduce the Jaw in a Day (JIAD) approach as a novel surgical option. Methods: PubMed, Web of Science and Embase were searched systematically. From an initial pool of 261 articles, 13 studies met the inclusion criteria and were reviewed. Results: Thirteen mandibular IMT cases were identified in the literature. A new case is also presented: a 15-year-old female treated with surgical excision using the JIAD approach. At 12-month follow-up, oral function was restored with no disease recurrence. Discussion: Mandibular IMT is exceedingly rare. The JIAD approach offers immediate reconstruction with satisfactory functional outcomes, as supported by both the current case and the reviewed literature. Conclusions: The JIAD surgical approach may represent an effective management strategy for mandibular IMT. Further cases are needed to validate this approach and establish standardized treatment protocols. Full article

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) have dramatically transformed the clinical management of ALK-rearranged non-small cell lung cancer (NSCLC). Successive generations of ALK inhibitors have been developed to overcome resistance mediated by kinase domain mutations, culminating in the third-generation inhibitor lorlatinib. Despite these advances, resistance remains inevitable, and durable disease control is rarely achieved. While resistance driven by single ALK mutations has been extensively characterized and structurally classified, the emergence of compound ALK mutations under sequential TKI therapy represents a qualitatively distinct and insufficiently conceptualized resistance state. This issue is becoming more complex as lorlatinib is increasingly used in the first-line setting, where resistance may arise from an ALK TKI-naïve background rather than from tumors already shaped by sequential ALK inhibition. In this review, we propose a unified framework that integrates structural single ALK resistance mutations (Types 1–3) with compound ALK mutations (Type 4) as a distinct evolutionary entity. We argue that compound mutations mark a critical inflection point at which ALK dependency reaches its functional limit, explaining the failure of even highly potent inhibitors such as lorlatinib. Importantly, we discuss how certain compound mutations paradoxically restore sensitivity to earlier-generation TKIs, highlighting the value of structural interpretation over linear drug sequencing. Finally, we discuss the transition toward ALK-independent resistance and future strategies incorporating dynamic molecular monitoring and structure-agnostic therapies. This framework may help clinicians interpret resistance mechanisms and guide rational treatment selection in daily practice. Full article

Anaplastic lymphoma kinase (ALK) rearrangement is a well-established oncogenic driver alteration in non-small cell lung cancer (NSCLC), and ALK tyrosine kinase inhibitors (TKIs), particularly lorlatinib, have significantly improved the prognosis of ALK-positive NSCLC patients. Although high programmed death-ligand 1 (PD-L1) expression (≥50%) is generally associated with favorable responses to immune checkpoint inhibitors (ICIs), PD-L1 has not been shown to reliably predict ICI benefit in ALK-rearranged disease, and optimal management after ALK TKI resistance remains challenging. Herein, we report a case of an elderly patient with ALK-rearrangement and exceptionally high PD-L1 expression (TPS ≥ 95%) NSCLC who experienced disease progression following first-line lorlatinib with genetically confirmed MET amplification. The patient subsequently received an exploratory combination of continued lorlatinib plus envafolimab and achieved partial response (PR) with manageable tolerability after 4 months, highlighting a potential sequential strategy that may warrant further investigation in select ALK-positive NSCLC patients exhibiting both bypass pathway activation and exceptionally high PD-L1 expression. Full article

Background: Targeted therapies directed against oncogenic drivers have substantially improved outcomes for patients with epidermal growth factor receptor (EGFR)-mutant and anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC). Despite high initial response rates, most patients ultimately develop acquired resistance to tyrosine kinase inhibitors (TKIs), reflecting complex biological adaptations under therapeutic pressure. Methods: This narrative review synthesizes experimental, translational, and clinical studies examining how environmental and occupational respiratory exposures may influence resistance mechanisms in EGFR- and ALK-driven NSCLC. The review emphasizes exposure-associated signaling plasticity, inflammatory microenvironmental modulation, metabolic reprogramming, and pharmacokinetic alterations. Results: Recent evidence suggests that respiratory exposures, including cigarette smoke, air pollution, diesel exhaust, and occupational inhalational toxicants, can modulate oncogenic signaling networks relevant to resistance to targeted therapies. These mechanisms include aberrant EGFR activation, bypass signaling through the mesenchymal–epithelial transition receptor (MET) and SRC pathways, epithelial–mesenchymal transition (EMT), adaptive kinome remodeling, and exposure-associated inflammatory signaling, all of which may influence tumor evolution and therapeutic response. Conclusions: This review introduces a novel exposome-driven conceptual framework integrating environmental exposures with signaling plasticity and resistance evolution in oncogene-driven NSCLC. These findings support the concept that the respiratory exposome may represent an underrecognized modifier of targeted therapy response. Incorporating structured exposure assessment into precision oncology approaches may refine risk stratification and inform exposure-aware therapeutic strategies. Full article

Pulmonary arterial hypertension (PAH) and cancer share high mortality and complex prognoses. Due to PAH’s rarity, these parallels may be underrecognized by healthcare stakeholders. This study explored similarities between PAH and cancer across epidemiological, clinical, therapeutic, and healthcare resource utilization (HCRU) considerations. A four-step approach was employed: (1) inclusion/exclusion criteria were applied to identify potential PAH cancer analogs; (2) characteristics for comparison were categorized as epidemiologic, clinical, therapeutic landscape, and HCRU; (3) a targeted literature review extracted data on disease characteristics; (4) a similarity ranking was calculated as the absolute difference between each cancer’s and PAH’s characteristics. Fourteen cancers met the inclusion criteria. Well-differentiated thyroid cancer (WDTC) had the highest number (5) of characteristics closest to PAH. WDTC and medullary thyroid cancer were most similar to PAH in epidemiology; gastrointestinal stromal tumor was most similar in clinical and HCRU characteristics, and anaplastic lymphoma kinase-positive (ALK+) non-small-cell lung cancer and renal cell carcinoma were most similar in therapeutic landscape. Although no single cancer fully mirrors PAH, the identification of multiple analogs underscores PAH’s multidimensional complexity and confirms its overlap with oncological conditions. Cancer analogs could serve as a valuable framework for enhancing recognition of PAH’s clinical, therapeutic, and HRCU implications among healthcare stakeholders. Full article

Background: Non-small cell lung cancer (NSCLC) is the most prevalent form of malignancy and the leading cause of cancer-related fatalities. In clinical practice, metastatic sites are identified on a case-by-case basis. ALK rearrangements are detected in 3–5% of NSCLC cases and are known to have a tendency (tropism) to metastasize to the brain. Methods: Data from 81 ALK-positive and 91 ALK-negative metastatic NSCLC patients were retrospectively analyzed. Systemic markers, including HALP score, NLR, PLR, LMR, and LDH, were calculated from blood tests at the time of metastasis. Optimal cut-off values were determined using ROC analysis. Survival outcomes and prognostic factors were assessed using Kaplan–Meier and Cox regression analyses. Results: ALK-positive patients were significantly associated with female gender (p = 0.002), non-smoking status (p = 0.001), adenocarcinoma histology (p = 0.001), and a higher incidence of brain metastases (p = 0.001). In univariate analysis, age, time to metastasis, liver metastasis, and NLR were prognostic for survival. Crucially, multivariate analysis identified liver metastasis as an independent predictor of poor prognosis (HR = 1.618; 95% CI: 1.050–2.494; p = 0.029), indicating a 61.8% increased risk of death or progression. While inflammation markers (NLR, HALP, PLR, LMR) did not predict metastasis to specific sites, elevated LDH levels were significantly associated with liver metastasis (p = 0.007). Conclusion: ALK-positive NSCLC demonstrates a marked CNS tropism; however, liver metastasis remains a more critical adverse prognostic factor than brain metastasis in real-world settings. While routine inflammation markers showed limited utility in predicting site-specific metastasis, LDH levels correlated significantly with liver involvement. Aggressive management strategies are warranted for ALK-positive patients presenting with liver metastases. Full article

Background: Advances in molecular pathology have transformed NSCLC (Non-Small Cell Lung Cancer) diagnosis, prognosis, and treatment by enabling precise tumor characterization and targeted therapeutic strategies. We review key genomic alterations in NSCLC, including EGFR (epidermal growth factor receptor) mutations, ALK (anaplastic lymphoma kinase) and ROS1 (ROS proto-oncogene 1) rearrangements, BRAF (B-Raf proto-oncogene serine/threonine kinase) mutations, MET (mesenchymal–epithelial transition factor) alterations, KRAS (Kirsten rat sarcoma) mutations, HER2 (human epidermal growth factor receptor 2) alterations and emerging NTRK (neurotrophic receptor tyrosine kinase) fusions and AXL-related pathways. Methods: A total of 48 patients with NSCLC was analyzed, including 22 women and 26 men (mean age 70 years, range 44–86). Tumor specimens were classified histologically as adenocarcinomas (n = 81%) or squamous cell carcinomas (n = 19%). Smoking history, PD-L1 (programmed death-ligand 1) expression, and genetic alterations were assessed. NGS (Next-generation sequencing) identified genomic variants, which were classified according to ACMG (American College of Medical Genetics and Genomics) guidelines. Results: The cohort consisted of 29 former smokers, 13 current smokers, and 5 non-smokers (12%), with a mean smoking burden of 33 pack years. PD-L1 TPS (tumor proportion score) was ≥50% in 10 patients, ≥1–<50% in 22, and <1% in 15 patients. In total, 120 genomic variants were detected (allele frequency ≥ 5%). Of these, 52 (43%) were classified as likely pathogenic or pathogenic, 48 (40%) as variants of unknown significance, and 20 (17%) as benign or likely benign. The most frequently altered genes were TP53 (tumor protein p53) (31%), KRAS and EGFR (15% each), and STK11 (serine/threonine kinase 11) (12%). Adenocarcinomas accounted for 89% of all alterations, with TP53 (21%) and KRAS (15%) being most common, while squamous cell carcinomas predominantly harbored TP53 (38%) and MET (15%) mutations. In patients with PD-L1 TPS ≥ 50%, KRAS mutations were enriched (50%), particularly KRAS G12C and G12D, with frequent co-occurrence of TP53 mutations (20%). No pathogenic EGFR mutations were detected in this subgroup. Conclusions: Comprehensive genomic profiling in NSCLC revealed a high prevalence of clinically relevant mutations, with TP53, KRAS and EGFR as the dominant drivers. The strong association of KRAS mutations with high PD-L1 expression, irrespective of smoking history, highlights the interplay between genetic and immunological pathways in NSCLC. These findings support the routine implementation of broad molecular testing to guide precision oncology approaches in both adenocarcinoma and squamous cell carcinoma patients. Full article

Background/Objectives: Brain metastases (BM) are a major challenge in the treatment of non-small cell lung cancer (NSCLC), particularly among patients with anaplastic lymphoma kinase rearrangements (ALK+ NSCLC), where incidence can reach up to 60% during the course of the disease. This study used in silico systems biology and artificial intelligence-based modeling to investigate the mechanistic effects of brigatinib, a second-generation ALK inhibitor, on metastatic processes in both primary tumors (PT) and established BM. Methods: We applied the Therapeutic Performance Mapping System (TPMS) technology, which integrates systems biology and artificial intelligence, to simulate the impact of brigatinib on metastasis-associated pathways in PT and BM of ALK+ NSCLC patients. Results: In these simulations, brigatinib was predicted to modulate a broad set of proteins implicated in metastasis in both PT and BM, acting mainly through IGF1R, EGFR, FLT3, and ROS1, in addition to its known target ALK. Conclusions: These results suggest brigatinib’s potential to impact key pathways involved in metastatic progression and intracranial disease control. Overall, this study provides insights into brigatinib’s multifaceted role in targeting metastatic processes in ALK+ NSCLC, underscoring its potential benefits in both PT and BM. Nonetheless, further experimental and clinical studies would confirm our results and the potential of in silico models reported here. Full article

Anaplastic lymphoma kinase (ALK), a member of the receptor tyrosine kinase family, plays a central oncogenic role in the initiation and progression of diverse malignancies. Aberrant ALK activation generally results from structural alterations or dysregulated expression, leading to persistent activation of downstream signaling pathways that drive tumor cell proliferation, survival, and metastasis. ALK gene abnormalities predominantly encompass fusions, point mutations, and amplifications, with EML4-ALK-positive non–small cell lung cancer representing a canonical example. The advent of ALK-targeted inhibitors has constituted a major therapeutic milestone for ALK-positive tumors. From first-generation Crizotinib to third-generation Lorlatinib, successive agents have been refined for target selectivity, central nervous system penetration, and coverage of resistance-associated mutations, substantially improving patient survival and intracranial disease control. Nonetheless, the emergence of acquired resistance remains an overarching challenge, mediated by secondary kinase domain mutations, activation of bypass signaling pathways, and tumor phenotypic transformation. This review presents an integrative synthesis of ALK-targeted therapeutic developments, elucidates underlying resistance mechanisms, and surveys emerging strategies, providing a comprehensive perspective on current advances and future directions in precision management of ALK-driven malignancies. Full article

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy with a five-year survival rate of 3–15% and limited effective treatment options for most patients. Approximately 5–10% of cases are wild-type KRAS and are more likely to harbor rare alterations, including gene fusions involving anaplastic lymphoma kinase (ALK), ROS Proto-Oncogene 1 (ROS1), neurotrophic tyrosine receptor kinase (NTRK), Rearranged During Transfection (RET), Fibroblast Growth Factor Receptor (FGFR), or Neuregulin 1 (NRG1) genes, as well as germline mutations in DNA repair genes. This review integrates current evidence on the prevalence, molecular profile, and clinical significance of gene fusions, amplification, and somatic/germline mutations in PDAC, with a particular focus on the wild-type KRAS subgroup. Clinical trial data and case reports indicate that these alterations can enhance patient susceptibility to targeted therapies. Currently, selpercatinib, larotrectinib, and repotrectinib are approved by the FDA for the treatment of certain solid tumors harboring specific gene fusions. Recent studies on zenocutuzumab resulted in the FDA-accelerated approval for NGR1 fusion-positive NSCLC and PDAC. Germline mutations may specifically increase responsiveness to poly(ADP-ribose) polymerase (PARP) inhibitors or platinum-based treatments. Comprehensive genomic profiling, incorporating fusion detection and germline testing, is essential to identify patients who may benefit from precision-based approaches. Full article