Cancer Chemotherapy and Pharmacology最新文献

{"title":"The value of target-site physiologically-based pharmacokinetics for high-affinity small molecules: a mechanistic foundation for precision dosing in oncology and hematology.","authors":"Suzanne van der Gaag, Daniela E Oprea-Lager, André N Vis, Harry Hendrikse, Imke H Bartelink","doi":"10.1007/s00280-026-04925-6","DOIUrl":"10.1007/s00280-026-04925-6","url":null,"abstract":"<p><p>For decades, oncology dose selection has been guided by the maximum tolerated dose (MTD) and plasma pharmacokinetics (PK), reflecting assumptions appropriate for classical cytotoxic chemotherapies. However, the advent of high-affinity, targeted therapies, including kinase inhibitors, epigenetic modulators, and radioligands challenges this paradigm. These agents achieve robust target engagement at doses far below the MTD, and systemic plasma concentrations often fail to reflect pharmacologically relevant exposure at tumor or hematologic sites. Physiologically-based pharmacokinetic (PBPK) modeling, extended to incorporate target-site dynamics, offers a mechanistic framework linking dose, systemic exposure, and local pharmacology. By integrating tissue physiology, drug properties, and target interactions, target-site PBPK provides insights into heterogeneous tumor penetration, intracellular distribution, and variable target occupancy that plasma PK alone cannot capture. Clinical examples, such as PSMA-targeted radioligands and tyrosine kinase inhibitors, illustrate how these models can inform rational dose selection, optimize ligand design, and guide individualized therapy. As oncology moves toward mechanism-driven, biology-aligned development, target-site PBPK represents a pivotal tool for translating preclinical insights into patient-specific dosing strategies and for redefining the standard of precision pharmacology.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364821/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429880","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacologic de-escalation of dexamethasone during weekly paclitaxel: a randomized phase III trial evaluating safety, endocrine effects, and quality of life.","authors":"Vanessa Armenio Scontre, Marcos Tadashi Kakitani Toyoshima, Maria Del Pilar Estevez-Diz","doi":"10.1007/s00280-026-04920-x","DOIUrl":"10.1007/s00280-026-04920-x","url":null,"abstract":"<p><strong>Objective: </strong>Dexamethasone is routinely used as premedication during weekly paclitaxel to prevent hypersensitivity reactions; however, prolonged corticosteroid exposure may induce clinically relevant metabolic, endocrine, and patient-reported adverse effects. This study evaluated whether selective omission of dexamethasone after the second paclitaxel infusion is safe and explored its effects on quality of life, metabolic/endocrine parameters, and short-term oncologic outcomes, including recurrence and disease-related mortality.</p><p><strong>Methods: </strong>In this prospective, randomized, open-label phase III trial, 86 women with stage I-III breast cancer receiving neoadjuvant or adjuvant AC-T or AC-TH chemotherapy were randomized 1:1 to standard dexamethasone premedication or omission after the second weekly paclitaxel infusion. The primary endpoint was safety, defined by hypersensitivity reactions and adverse events. Secondary and exploratory endpoints included patient-reported quality of life using the EORTC QLQ-C30, metabolic and endocrine parameters, and short-term oncologic outcomes. Longitudinal changes were analyzed using generalized estimating equations.</p><p><strong>Results: </strong>Eighty-four patients were included in the final analysis. No hypersensitivity reactions occurred after dexamethasone omission, and treatment completion rates were comparable between groups. After a median follow-up of 3.15 years, recurrence and disease-related mortality were similar between groups in descriptive analyses. The omission strategy was associated with improvements in role functioning and reduced worsening of pain (p = 0.02), constipation (p = 0.01), and nausea/vomiting (p = 0.03). No statistically significant differences were observed for emotional or physical functioning. Endocrine analyses demonstrated reduced IGF-1 levels and a trend toward lower insulin levels. These secondary analyses should be interpreted as exploratory.</p><p><strong>Conclusion: </strong>Selective omission of dexamethasone after the second weekly paclitaxel infusion was safe and well tolerated in this randomized trial. The findings support the feasibility of a corticosteroid-sparing strategy during weekly paclitaxel and suggest potential benefits in selected patient-reported and endocrine outcomes, which warrant confirmation in larger studies.</p><p><strong>Trial registration: </strong>NCT04350229, registered on 16 April 2020.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13364796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148429883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Anti-PD-1 single-chain variable fragments in cancer immunotherapy: from molecular engineering to clinical translation.","authors":"Zahraa AlKhafaje, H Malathi, Aniruddh Dash, J Precilla Selvakumari, Gurjant Singh, Aashna Sinha, Muath Suliman, Aseel Smerat","doi":"10.1007/s00280-026-04911-y","DOIUrl":"https://doi.org/10.1007/s00280-026-04911-y","url":null,"abstract":"<p><p>The programmed death-1 (PD-1) immune checkpoint is a core regulator of T-cell exhaustion and immune evasion in cancer. While PD-1/PD-L1 monoclonal antibodies have changed the landscape of cancer immunotherapy, there are barriers to broader application due to their large size, potential for systemic toxicities, and high production costs. In this review article, we will focus on therapeutic development, functional applications, and translational advances of anti-PD-1 single-chain variable fragments (scFvs). Advances in phage-display libraries, immunization methods, and antibody engineering have helped develop high-affinity scFvs with novel structural and mechanistic properties. Direct functional applications incorporating anti-PD-1 scFvs are bispecific and trispecific constructs, antibody-drug conjugates (ADCs), immunotoxins, nanoparticles, and biological vector carriers that incorporate checkpoint blockade with targeted cytotoxicity or immunostimulation. Engineered immune cells, such as armored CAR-Ts, NK cells, and MSCs, can secrete or display anti-PD-1 scFvs within the tumor to provide localized checkpoint inhibition, enhance effector-cell persistence, and remodel the tumor microenvironment. Oncolytic and non-replicating viral vectors can further confine scFv activity to tumors, coupling checkpoint blockade with oncolysis, cytokine expression, or bispecific T-cell engagers. Early-phase clinical trials are currently studying TILs and CAR-TILs engineered to secrete scFvs and oncolytic HSV-1 encoding multifunctional checkpoint payloads across a variety of solid tumors. Taken together, anti-PD-1 scFvs represent a modular platform for localized checkpoint inhibition and potentially improved cost-effectiveness compared with systemic antibodies. Future work should prioritize rational combination strategies and well-designed clinical trials that integrate anti-PD-1 scFv platforms with other immunotherapies and standard treatments to maximize clinical benefit.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148410586","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Pharmacokinetics of asciminib in a patient with chronic myeloid leukemia undergoing maintenance hemodialysis.","authors":"Maiko Abumiya, Ko Abe, Atsushi Watanabe, Naoto Takahashi","doi":"10.1007/s00280-026-04919-4","DOIUrl":"10.1007/s00280-026-04919-4","url":null,"abstract":"<p><p>Asciminib (ASC) is a novel BCR::ABL1 tyrosine kinase inhibitor that binds to the ABL myristoyl pocket. Although dose adjustments for renal impairment are generally considered unnecessary, pharmacokinetic data for patients with end-stage renal disease or those on dialysis are limited. A 72-year-old man with chronic phase chronic myeloid leukemia undergoing maintenance hemodialysis for chronic renal failure was treated with ASC. Owing to cardiovascular risk, treatment was initiated at a reduced dose of 40 mg once daily. A major molecular response was achieved within 3 months without adverse events. Pharmacokinetic analysis revealed a delayed apparent T_max (> 4 h), suggesting prolonged absorption. ASC concentrations did not decrease during dialysis sessions compared with non-dialysis days. The median trough concentration was 89.0 ng/mL, with a coefficient of variation of 30.9%. ASC demonstrated negligible dialyzability, likely because of its high plasma protein binding (97.3%). However, the study revealed a significantly delayed apparent T_max and high intra-individual variability in plasma concentrations. These findings suggest that clinicians should prioritize monitoring for delayed gastrointestinal absorption and potentially reduced bioavailability in patients undergoing maintenance hemodialysis, rather than focusing on drug removal by dialysis.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13342300/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395865","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Successful oral desensitization to temozolomide in a patient with immediate hypersensitivity reaction.","authors":"Ece Şahinoğlu, Muhittin Akarsu, Selma Yalçın, Dilşad Mungan, Zeynep Celebi Sozener","doi":"10.1007/s00280-026-04922-9","DOIUrl":"10.1007/s00280-026-04922-9","url":null,"abstract":"<p><p>Temozolomide (TMZ) is an oral alkylating agent that represents a cornerstone therapy for glioblastoma and other high-grade gliomas. Although TMZ is generally well tolerated, hypersensitivity reactions (HSRs), including urticaria, have rarely been reported and may lead to treatment interruption. Rapid drug desensitization (RDD) offers a potential strategy to enable continuation of essential therapy; however, standardized protocols for TMZ are limited. Here, we present a 46-year-old woman with glioblastoma who developed widespread urticaria during maintenance TMZ therapy. The reaction developed within four hours of the last dose and completely resolved following treatment with corticosteroids and antihistamines within 24 h. Based on clinical history and lesion characteristics, an immediate HSR to TMZ was considered. As no alternative treatment options were available, an oral RDD protocol targeting a dose of 240 mg was prepared. The protocol included stepwise dose escalation using diluted oral solutions followed by capsule administration, with premedication using cetirizine and methylprednisolone. Desensitization was successfully completed without breakthrough reactions, and the protocol was repeated in two consecutive cycles without complications. Our protocol provides detailed information on drug preparation, dose increments, and administration intervals, supporting its reproducibility and feasibility. This case contributes to the limited literature by demonstrating that oral RDD can be safely and effectively performed in patients with TMZ-induced urticaria. The successful repetition of desensitization further supports the safety of this approach. This protocol may assist clinicians in maintaining first-line TMZ therapy in patients with HSRs, thereby preventing unnecessary treatment interruptions and improving clinical outcomes.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148395961","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Off-target anti-leukemic effects of antibiotics: mechanisms and therapeutic insights.","authors":"Jason Charamis, Nikolaos Katzilakis, Eftichia Stiakaki, Ioannis Kyriakidis","doi":"10.1007/s00280-026-04916-7","DOIUrl":"10.1007/s00280-026-04916-7","url":null,"abstract":"<p><p>Antibiotics are among the transformative advances in medicine, but many interact with mammalian cellular targets and pathways beyond their antimicrobial activity. A clinically important expression of these off-target effects is hematologic toxicity, including immune-mediated cytopenias and direct bone marrow suppression. This narrative review examines whether the same biology that injures normal hematopoietic cells can, in selected contexts, reveal therapeutically exploitable vulnerabilities in leukemia. We synthesize molecular, clinical, and preclinical evidence and organize it into an integrative framework linking mitochondrial translation inhibition, mitonuclear imbalance, oxidative phosphorylation failure, reactive oxygen species generation, DNA/topoisomerase stress, autophagy and lysosomal-flux blockade, and apoptosis modulation with both hematotoxicity and antileukemic activity. The strongest preclinical evidence supports selected tetracyclines, macrolides, and oxazolidinones, whereas evidence for beta-lactams, glycopeptides, polymyxins, rifamycins, fluoroquinolones, and folate-pathway agents remains more limited or largely hypothesis-generating. Importantly, antibiotic-induced cytopenia should not be interpreted as proof of leukemia selectivity: immune-mediated toxicity, supratherapeutic in vitro exposure, normal progenitor injury, pharmacokinetic constraints, microbiome effects, and resistance mechanisms all narrow the translational window. Overall, antibiotic hematotoxicity is best viewed as a biologically informative signal that can guide mechanism-based repurposing and combination strategies, but clinical development requires rigorous pharmacokinetic/pharmacodynamic validation, normal hematopoietic comparators, and biomarker-driven patient selection.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389975","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The use of pharmacodynamic results for recommended phase II decision making in oncology clinical trials.","authors":"A C Kanhailal, M J J Lucassen, T Schutte, W Zwart, A D R Huitema, N Steeghs","doi":"10.1007/s00280-026-04924-7","DOIUrl":"10.1007/s00280-026-04924-7","url":null,"abstract":"<p><strong>Introduction: </strong>Pharmacodynamic analyses are increasingly important to early-phase oncology drug development, however these analyses use invasive methods to collect patient material. Yet, their role in guiding recommended phase II dose (RP2D) decisions remains unclear. Therefore, this review evaluates how pharmacodynamic analyses assisted the determination of the recommended phase II dose (RP2D) in first-in-human cancer trials of small-molecule agents.</p><p><strong>Method: </strong>First-in-human dose finding clinical trials of single-agent small-molecule anticancer therapies published between 2022 and 2025 that included pharmacodynamic assessments, were investigated. Clinical trials were evaluated for correlation of pharmacodynamic results at the analyzed doses and their influence in the RP2D decision-making process.</p><p><strong>Results: </strong>In total, 535 records were identified and 34 articles, reporting on 34 separate trials, were included. A correlation was found between the pharmacodynamic results and the analyzed dose levels in 92% (n = 31/34). However, only half of the clinical trials (n = 17/34) reported their pharmacodynamic results in the RP2D decision-making process, while 41% (n = 14/34) did not. In most of the clinical trials that did not use their pharmacodynamic results in the RP2D decision-making process, only one pharmacodynamic analysis was performed (n = 9/14, 64%) and they often determined their RP2D solely based on safety and/or tolerability (n = 7/14, 50%). Invasive procedures were often performed without clear utilization of pharmacodynamic data, raising ethical considerations.</p><p><strong>Conclusion: </strong>These findings underscore the need for appropriate sample sizes planning and validated, fit-for-purpose pharmacodynamic assays to ensure meaningful use in dose selection, optimizing patient benefit and trial design.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13337676/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148389982","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Composition and structure of stratum corneum intercellular lipids in patients with osimertinib-induced hand-foot syndrome.","authors":"Michiaki Nakajo, Tomonobu Uchino, Kazuhiro Asada, Ichiro Hatta, Ryuji Yumoto, Mayuko Okada, Yuna Iwano, Yui Nabekura, Yasunori Miyazaki, Kanami Ikeda, Tasuku Yokoyama, Yoshiyuki Kagawa, Daiki Tsuji","doi":"10.1007/s00280-026-04915-8","DOIUrl":"https://doi.org/10.1007/s00280-026-04915-8","url":null,"abstract":"<p><strong>Purpose: </strong>Osimertinib (OSM), a third-generation epidermal growth factor receptor tyrosine kinase inhibitor, causes skin disorders, such as hand-foot syndrome (HFS), which impairs skin barrier function. Stratum corneum (SC) lipids play an important role in skin barrier function. This study aimed to compare the SC lipid composition and structure of healthy participants with those of patients with OSM-induced HFS.</p><p><strong>Methods: </strong>Overall, 47 patients with non-small cell lung cancer were enrolled in this study. All patients received 80 mg/day OSM orally and completed the 56-day prospective observation period. SC samples were obtained from seven patients with OSM-induced HFS (OSC). SC lipid composition (ceramide [CER] and free fatty acids [FFAs]) and structure were analyzed using ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and synchrotron X-ray diffraction, respectively.</p><p><strong>Results: </strong>In healthy SC (HSC), the lipids formed two lamellar phases. Hexagonal and orthorhombic hydrocarbon chain packing was observed in the lateral lipid organization. However, in the OSC, these structures almost disappeared. UPLC-MS/MS analysis revealed that the composition of CER and FFA differed between OSC and HSC and that the carbon chain length of SC lipid components in OSCs was lower compared with that in HSCs. However, no significant differences were observed in the CER levels of the esterified ω-hydroxy fatty acid class, which is involved in the formation of long-period lamellar structures, between the two groups.</p><p><strong>Conclusion: </strong>OSM induces changes in SC lipid structure due to changes in SC lipid composition and a decrease in carbon chain length in OSCs, resulting in impaired barrier function.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148366850","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CDK4/6 inhibitor-statin interaction and rhabdomyolysis in breast cancer treatment: a case-based systematic review.","authors":"Rafael Batista João, Leonardo Ribeiro Soares, Paulo César Ragazzo, Ruffo Freitas-Junior","doi":"10.1007/s00280-026-04913-w","DOIUrl":"10.1007/s00280-026-04913-w","url":null,"abstract":"<p><strong>Purpose: </strong>Cyclin-dependent kinase (CDK) 4/6 inhibitors have significantly advanced the treatment of hormone receptor-positive, HER2-negative metastatic breast cancer, improving outcomes. However, their concurrent use with statins, a widely prescribed class of drugs, may pose a risk of rhabdomyolysis due to pharmacokinetic and pharmacodynamic interactions. This systematic review analyzes reported cases to characterize clinical presentations, therapeutic approaches, and outcomes.</p><p><strong>Methods: </strong>A systematic search of PubMed, Embase, Scopus, and Web of Science from inception to January 2026 for case reports and case series documenting rhabdomyolysis in patients treated with CDK4/6 inhibitors. Data on demographics, clinical features, laboratory findings, management strategies, and outcomes were extracted. Quality assessment of the included cases was performed using the Joanna Briggs Institute Critical Appraisal Checklist.</p><p><strong>Results: </strong>Seven case reports involving female patients aged 55-81 years were analyzed. All patients were treated for metastatic breast cancer with CDK4/6 inhibitors (ribociclib, palbociclib, or abemaciclib) alongside statins (simvastatin, atorvastatin, or rosuvastatin). Rhabdomyolysis onset ranged from 3 days to 48 months after initiation of combination therapy, or shortly after statin dose escalation in the setting of long-term CDK4/6 inhibitor use. Clinical presentations included severe myalgia, muscle weakness, and dark urine, with creatine kinase levels ranging from 3,070 to 47,000 U/L. Acute kidney injury was reported in five cases. Management primarily involved cessation of the implicated drugs and aggressive hydration, with adjunctive treatments such as corticosteroids, plasma exchange, or intravenous immunoglobulin. Five patients recovered fully, one had partial recovery with persistent renal dysfunction, and one fatality was reported.</p><p><strong>Conclusions: </strong>Rhabdomyolysis due to CDK4/6 inhibitor-statin interactions is a rare but potentially life-threatening complication. Vigilant monitoring, timely intervention, and tailored treatment strategies are essential for preventing complications and improving patient outcomes.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13319690/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148359659","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ALK rearrangements and resistance mutations in non-small cell lung cancer: molecular mechanisms and therapeutic implications.","authors":"Palani Bharath, Sailakshmi Iyer, Ankitha Vadi Velu, D Thirumal Kumar","doi":"10.1007/s00280-026-04910-z","DOIUrl":"https://doi.org/10.1007/s00280-026-04910-z","url":null,"abstract":"<p><p>Anaplastic lymphoma kinase (ALK) gene rearrangements represent one of the well-characterized oncogenic drivers in non-small cell lung cancer (NSCLC), with the EML4-ALK fusion being the most common and clinically significant rearrangement. ALK inhibitors, including crizotinib, ceritinib, alectinib, brigatinib, and lorlatinib has significantly improved clinical outcomes in ALK-rearranged NSCLC patients. However, the emergence of drug resistance remains inevitable which is mediated by either on-target mechanisms or off-target mechanisms. Mutations in the kinase domain, particularly in the solvent-front and gatekeeper regions alter the conformation of the ATP-binding site, leading to reduced binding affinity of ALK inhibitors. Importantly, G1202R-associated compound mutations confer high-level resistance, thereby limiting the effectiveness of currently available TKIs and posing a significant challenge in the clinical settings. In addition to acquired secondary mutations, the presence of the EML4-ALK variant 3 further worsens the prognosis and increases the risk of metastasis. Moreover, even when ALK is inhibited, activation of bypass signaling pathways can promote tumor progression via off-target mechanisms. To overcome these resistance mechanisms, the development of novel therapeutic strategies are required. By integrating structural biology, mutation evolution patterns, and emerging therapeutic approaches, this review underscores the need for next-generation inhibitors to overcome resistance and improve long-term outcomes in patients with ALK-positive NSCLC.</p>","PeriodicalId":9556,"journal":{"name":"Cancer Chemotherapy and Pharmacology","volume":"96 1","pages":""},"PeriodicalIF":2.5,"publicationDate":"2026-06-29","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148344017","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}