Investigational New Drugs最新文献

{"title":"Phase I results of a multicenter, open-label, dose de-escalation and expansion study of gemcitabine and cisplatin with ivosidenib or pemigatinib for advanced cholangiocarcinoma.","authors":"Fen Saj, Tanios S Bekaii-Saab, Milind Javle, Joseph J Larson, Mitesh J Borad, Shubham Pant","doi":"10.1007/s10637-026-01602-6","DOIUrl":"10.1007/s10637-026-01602-6","url":null,"abstract":"<p><p>Cholangiocarcinoma (CCA) is a rare and aggressive biliary tract cancer with a poor prognosis. Despite recent advancements in molecularly targeted therapies for patients with IDH1 mutations and FGFR2 fusions, the efficacy of integrating these agents with first-line chemotherapy has not been established. This multicenter, Phase Ib dose de-escalation study, conducted prior to the establishment of chemoimmunotherapy as the standard first-line therapy, evaluated the safety and preliminary efficacy of combining ivosidenib or pemigatinib with gemcitabine and cisplatin in patients with advanced CCA. Eligible patients with no disease progression after three cycles of standard chemotherapy were assigned to receive either ivosidenib or pemigatinib based on their mutation status and chemotherapy. The primary endpoints were to evaluate safety, tolerability, the maximum tolerated dose, and the recommended Phase II dose. Secondary endpoints included progression-free survival (PFS), overall survival (OS), and best response profile. The study opened in January 2020 and closed early in November 2022, enrolling eight patients - seven in the ivosidenib arm (Arm A) and one in the pemigatinib arm (Arm B). Enrollment in Arm B was constrained due to challenges in identifying FGFR2 fusion/rearrangement-positive patients in the first-line setting. Treatment-related toxicities of grade 3 or higher occurred in four patients (66.7%) in Arm A. Regarding efficacy, one patient (16.7%) in Arm A achieved a partial response, while the remaining five had stable disease, with a median progression-free survival (PFS) of 15.4 months in Arm A and a median overall survival (OS) of 22.9 months. Given the selection bias and small sample size, these efficacy analyses must be interpreted with caution. Adding ivosidenib to gemcitabine and cisplatin in this study demonstrated a challenging safety profile in advanced CCA. Further research and dose optimization are warranted to confirm these findings and optimize the integration of targeted therapies into first-line regimens.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"48-55"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"146165176","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical features, treatment and outcomes of pembrolizumab induced autoimmune hemolytic anemia.","authors":"Jieqiong Liu, Wei Sun, Chunjiang Wang","doi":"10.1007/s10637-026-01596-1","DOIUrl":"10.1007/s10637-026-01596-1","url":null,"abstract":"<p><p>To explore the clinical characteristics of pembrolizumab induced autoimmune hemolytic anemia (AIHA) and to provide references for diagnosis, treatment and prognosis. Case reports and case series of pembrolizumab induced AIHA were collected by searching the database and the clinical data of patients were summarized for statistical analysis up to August 31, 2025. Sixteen cases (55.2%) of male patients and 13 cases (44.8%) of female patients were included, with a median age of 69 years (36,85). The median time to develop AIHA after the first administration was 30 days (range 10,780), and the median cycle was 2.5 cycles (range 1,33). Clinical symptoms can be manifested as fatigue (13.8%), shortness of breath (10.3%), dyspnea (10.3%) and dizziness (6.9%). Direct antiglobulin test showed negative results (17.2%). Warm AIHA accounted for 44.8% of pembrolizumab induced AIHA. Peripheral blood smear examination showed spherocytes (20.7%), red cell agglutination (10.3%). After discontinuation of pembrolizumab and treatment with glucocorticoids (100%) and red blood cell infusion (69.0%), 96.5% of the patients achieved a treatment response. AIHA is a rare and serious complication of pembrolizumab. Clinicians should be aware of the possibility of AIHA occurrence during the treatment process. DAT negativity does not rule out pembrolizumab -induced AIHA. Glucocorticoids may be an important option for the treatment of AIHA. For refractory AIHA, second-line treatment needs to be initiated.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1-8"},"PeriodicalIF":3.4,"publicationDate":"2026-02-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145932818","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Phase 1 dose escalation trial of the selective adenosine A2B antagonist PBF-1129 in patients with metastatic non-small cell lung cancer.","authors":"Dwight H Owen, Ruohan Wu, Lai Wei, Mikhail Dikov, Shankar Suman, Po-Lan Su, Joseph Amann, Shuxiao Guan, Daniel Spakowicz, Catherine Schweitzer, Carly Pilcher, Michael B Smith, Sarah Ferguson, Julio Castro Palomino, Santiago Figueroa Pérez, Erin M Bertino, Peter G Shields, Kai He, Carolyn J Presley, Gregory A Otterson, William E Carson, David P Carbone","doi":"10.1007/s10637-025-01591-y","DOIUrl":"10.1007/s10637-025-01591-y","url":null,"abstract":"<p><p>The adenosinergic pathway represents a critical immunometabolic checkpoint within the tumor microenvironment of non-small cell lung cancer (NSCLC), contributing to immune suppression and therapeutic resistance. PBF-1129, an oral, selective A2B adenosine receptor (A2BAR) antagonist, was evaluated in a phase 1, open-label, dose-escalation trial (NCT03274479) in patients with advanced/metastatic NSCLC who had progressed on standard therapies. All patients had previously received chemotherapy and immune checkpoint blockade. Twenty-one patients received escalating doses (40-320 mg once daily), with no dose-limiting toxicities observed. The most frequently reported treatment related adverse events of any grade were lymphocytopenia (n = 8, 38.1%), vomiting (n = 8, 38.1%), anorexia (n = 6, 28.5%), and fatigue (n = 6, 28.5%). PBF-1129 showed dose-proportional pharmacokinetics and maintained plasma concentrations above the 90% maximal inhibitory concentration (IC₉₀) of A2BAR at 320 mg for 24 h, which was determined to be the recommended phase 2 dose (RP2D). Best response was stable disease in 3 out of 21 patients including 2 of 6 treated at RP2D. Immunophenotyping revealed post-treatment reductions in programmed cell death protein 1 (PD-1) expression on CD8⁺ T cells, which correlated with improved survival. The reduction of PD-1 expression on CD4⁺ T cells and decreased myeloid-derived suppressor cells were also associated with better outcomes. These findings suggest PBF-1129 is safe and modulates the systemic immune parameters, warranting further evaluation in combination with immune checkpoint blockade.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1211-1221"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12753538/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145667390","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A phase 2, open-label, single-arm study evaluating the combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed in patients with metastatic non-small cell lung cancer harbouring targetable genomic alterations who progressed on standard tyrosine kinase inhibitors.","authors":"Hoi Wai Chan, Chris Chun Long Tse, Yu-Chung Li, Roland Leung, Gin Wai Kwok, Jeffrey Sum Lung Wong, Karen Hoi-Lam Li, Josephine Wing Yan Tsang, Cho Wing Li, Jenny Wai Yan Lo, Vikki Tang, Rina Hui, Thomas Yau, James Chung Man Ho, Joanne Wing Yan Chiu","doi":"10.1007/s10637-025-01589-6","DOIUrl":"10.1007/s10637-025-01589-6","url":null,"abstract":"<p><p>Patients with metastatic non-small cell lung cancer (NSCLC) harbouring targetable genomic alterations who progressed on standard tyrosine kinase inhibitors (TKIs) have limited treatment options, with platinum-based chemotherapy offering modest efficacy. We evaluated the efficacy and safety of a novel combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed in this population. This phase 2, open-label, single-arm study enrolled patients with metastatic NSCLC with sensitizing epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK) or c-ROS oncogene 1 (ROS1) alteration who progressed on standard TKIs. Patients received a combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed. The primary endpoint was objective response rate (ORR) per RECIST 1.1. Secondary endpoints included progression free survival (PFS), overall survival (OS) and safety. Of the 24 patients screened, 19 were enrolled and included in the intention-to-treat population. Median follow-up time was 10.7 months (95% CI 4.4-11.9). ORR was 31.6% (6/19, 95% CI 12.6%-56.6%; all partial responses). Median PFS was 11.9 months (95% CI 4.3-not reached). Median OS was not reached. Most of the treatment-related adverse events (TRAEs) were grade 1-2, which occurred in 63% (12/19) of the patients. The most common TRAEs were hypothyroidism (31.6%), nausea (26.3%), neutropenia (26.3%), thrombocytopenia (26.3%) and anorexia (21.1%). The combination of pembrolizumab, lenvatinib, carboplatin and pemetrexed showed modest efficacy and manageable toxicity in metastatic NSCLC patients with targetable genomic alterations who progressed on standard TKIs. NCT04989322.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1191-1200"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12753539/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ceralasertib, an ATR kinase inhibitor, as monotherapy in Japanese patients with advanced solid malignancies: Results from a phase 1 study.","authors":"Yasutoshi Kuboki, Nobuaki Matsubara, Hiromichi Nakajima, Takao Fujisawa, Takafumi Koyama, Jun Sato, Yuki Katsuya, Aleksandra Kmieciak, Daniel Slade, Kiyomi Iwata, Yusuke Takahashi, Masahiro Nii, Kosho Murayama, Toshio Kawata, Hisashi Kawasumi, Noboru Yamamoto","doi":"10.1007/s10637-025-01592-x","DOIUrl":"10.1007/s10637-025-01592-x","url":null,"abstract":"<p><strong>Background: </strong>Ceralasertib is an oral, selective, and potent inhibitor of ATR serine/threonine kinase, a key protein involved in cell cycle checkpoint regulation and DNA damage response. We report preliminary safety, tolerability, and pharmacokinetic data of ceralasertib monotherapy in Japanese patients with advanced solid tumors.</p><p><strong>Methods: </strong>In this phase 1, open-label study, patients orally received ceralasertib twice daily 240 mg on days 1-7 (Cohort 1) or 160 mg on days 1-14 (Cohort 2) of a 28-day cycle, respectively; both cohorts also received a single ceralasertib dose 4 days before Cycle 1. Patients were aged ≥ 18 years with solid malignancies refractory to standard therapies or for which no standard therapy exists. The primary objective was to determine ceralasertib safety; secondary objectives included assessing antitumor activity and pharmacokinetics. Exploratory objectives included biomarker analysis.</p><p><strong>Results: </strong>Twelve of 14 patients screened received ceralasertib. At data cutoff (August 17, 2023), all 12 patients had experienced at least one treatment-emergent adverse event (AE; grade ≥ 3, n = 3). One patient in each cohort had a dose-limiting toxicity; no AE-related deaths were reported. In total, 6 patients had a best objective response of stable disease (Cohort 1, n = 2; Cohort 2, n = 4). A trend suggesting dose-proportional increases in exposure following single and multiple administration of ceralasertib was observed.</p><p><strong>Conclusion: </strong>Ceralasertib monotherapy was generally well tolerated in Japanese patients with advanced solid tumors. The small number of patients enrolled prevents definitive conclusions on the efficacy of ceralasertib monotherapy to be made.</p><p><strong>Trial registration: </strong>ClinicalTrials.gov, NCT05469919. Registration date: May 18, 2022.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1235-1246"},"PeriodicalIF":2.7,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12753540/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145687325","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Multicenter retrospective study of selpercatinib treatment for advanced or recurrent RET fusion-positive non-small cell lung cancer in Japan.","authors":"Yasuhiro Mihashi, Kiyohide Komuta, Akihiro Tsukaguchi, Reiko Inada, Atsushi Yanagisawa, Yuhei Shimizu, Ken Yamamoto, Satoshi Tanaka, Naoko Katsurada, Takeshi Nakatani, Yuki Takeyasu, Taiichiro Otsuki, Satoshi Tetsumoto, Akihiro Tamiya, Takayuki Shiroyama, Motoko Tachihara, Kazumi Nishino, Takayasu Kurata, Masahide Mori","doi":"10.1007/s10637-025-01593-w","DOIUrl":"10.1007/s10637-025-01593-w","url":null,"abstract":"<p><strong>Background: </strong>Selpercatinib is the current standard of care for patients with recurrent or advanced RET fusion-positive non-small cell lung cancer (RET-NSCLC). However, real-world data on selpercatinib for RET-NSCLC are extremely limited, particularly in the Japanese population.</p><p><strong>Methods: </strong>This retrospective multicenter study enrolled 27 patients who were pathologically diagnosed with RET-NSCLC and started selpercatinib treatment between September 2021 and June 2024. Patients who had previously received other molecular-targeted drugs were excluded. Of the patients, 10 had received prior treatment and 17 had not.</p><p><strong>Results: </strong>As of August 31, 2024, the median follow-up period was 12.0 months (range 0.5-31.5 months). The objective response rate (ORR) was 100% (8/8 cases) in the previously treated group and 81% (13/16 cases) in the treatment-naïve group. The median progression-free survival (PFS) was 13.3 months (95% confidence interval [CI] 0.5-not evaluable [NE]) in the previously treated group and 23.5 months (95% CI 5.7-NE) in the treatment-naïve group. The median overall survival was 25.4 months (95% CI 0.5-NE) in the previously treated group and not reached (95% CI NE-NE) in the treatment-naïve group. No significant differences were observed in any of these comparisons. The most frequent grade 3 adverse event (AE) was increased ALT (n = 11, 41%), followed by increased AST (n = 7, 26%).</p><p><strong>Conclusions: </strong>In Japanese patients treated with selpercatinib, efficacy in whole patients was similar to the worldwide population, whereas AEs (especially liver dysfunction) was more severe than worldwide population. This result highlights the need for careful dose management strategies for Japanese patients.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1201-1210"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145573689","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"ABCB1 and ABCC10 polymorphisms predict sensitivity to first- and third-generation EGFR-TKIs in EGFR-mutant NSCLC.","authors":"Sanae Toda-Shiraga, Takehiro Uemura, Akihito Kakihara, Fumitaka Hashiba, Tatsuya Tanaka, Toshiyasu Ito, Tomohiro Onuki, Keima Ito, Yuta Mori, Kensuke Fukumitsu, Satoshi Fukuda, Yoshihiro Kanemitsu, Tomoko Tajiri, Hirotsugu Ohkubo, Ken Maeno, Akio Niimi, Tetsuya Oguri","doi":"10.1007/s10637-025-01594-9","DOIUrl":"10.1007/s10637-025-01594-9","url":null,"abstract":"<p><p>This study investigated the association between ATP-binding cassette (ABC) transporter gene polymorphisms and Epidermal Growth Factor Receptor (EGFR)- Tyrosine kinase inhibitor (TKI) sensitivity in non-small cell lung cancer (NSCLC). Our goal was to determine if these genetic variations could serve as valuable biomarkers for predicting treatment efficacy. We examined the associations between ABC transporter mRNA expression and EGFR-TKI sensitivity in 16 NSCLC cell lines. Expression of ABCB1, ABCG2, ABCC10, and ABCC11 was quantified by real-time PCR and correlated with IC₅₀ values of gefitinib and osimertinib. Additionally, associations between transporter gene single nucleotide polymorphisms (SNPs) (ABCB1 C1236T, ABCB1 C3435T, ABCG2 C421A, ABCC10 T2843C, ABCC11 G538A) and EGFR-TKI sensitivity were evaluated. To assess clinical relevance, blood samples from 109 gefitinib/erlotinib- and 54 osimertinib-treated patients were analyzed for these SNPs. While no significant correlation was found between mRNA expression and IC₅₀ values in cell lines, we did find that specific SNPs significantly correlated with drug cytotoxicity in vitro. Clinically, the ABCB1 C1236T T/T genotype was associated with prolonged PFS in patients on first-generation EGFR-TKIs, while the ABCC10 T2843C T/T genotype was linked to longer PFS with third-generation EGFR-TKIs. These findings suggest that ABC transporter SNPs could be valuable biomarkers for personalized medicine in NSCLC. These findings suggest that ABC transporter SNPs may serve as valuable biomarkers for predicting EGFR-TKI efficacy in NSCLC patients with EGFR mutations, which will contribute to personalized medicine.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1222-1234"},"PeriodicalIF":3.4,"publicationDate":"2025-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145668611","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sunvozertinib: a Promising Oral EGFR Inhibitor Approved for NSCLC with EGFR Ex20ins Mutations.","authors":"Kavita Sangwan, Gaurav Agarwal","doi":"10.1007/s10637-025-01588-7","DOIUrl":"10.1007/s10637-025-01588-7","url":null,"abstract":"<p><p>Lung cancer continues to be a significant health burden in the United States, with 2025 estimates indicating approximately 226,650 new cases and 124,730 deaths. NSCLC is the predominant histological subtype of lung cancer, representing approximately 80% to 85% of all diagnosed cases. Within the NSCLC cohort, the EGFR represents the most commonly altered tumor-initiating mutation, exhibiting the highest prevalence among actionable molecular aberrations. Ex20ins in the EGFR gene represent the third most common type of EGFR mutation, observed in approximately 0.3% to 2.9% of all NSCLC cases and 2% to 5% of EGFR-mutant NSCLC subtypes. In July 2025, the US FDA granted accelerated approval for sunvozertinib, an oral and irreversible EGFR tyrosine kinase inhibitor, for the treatment of NSCLC patients who have mutations in the EGFR Ex20ins. Sunvozertinib received conditional approval in China for the second-line NSCLC with mutations in the EGFR Ex20ins, based on safety and efficacy data derived from a Phase II clinical study. Before the approval of sunvozertinib, treatment approaches for EGFR Ex20ins-mutant patients with NSCLC were limited and largely suboptimal. Conventional EGFR-TKIs exhibited minimal clinical efficacy, primarily due to intrinsic structural resistance mechanisms conferred by these specific mutations. This manuscript focuses on the clinical studies that supported the USFDA accelerated approval of sunvozertinib, along with its ongoing and upcoming clinical trials, preclinical research, and other pharmacological aspects.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1177-1189"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145482238","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"BRPF1 inhibitor GSK6853 inhibits NSCLC cell proliferation via the JAK2/STAT3/CCNA2 axis to induce cell cycle arrest.","authors":"Jun Yang, Wei Ji, Lei Liao, Bingdong Jiang, Can Gao, Ying Huang, Zhen Mao, Li Ji, Fang Liu, Jianchang Zeng","doi":"10.1007/s10637-025-01585-w","DOIUrl":"10.1007/s10637-025-01585-w","url":null,"abstract":"<p><p>Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality worldwide, and current therapies offer limited efficacy for many patients. GSK6853, a selective inhibitor of the BRPF1, has shown promising anticancer activity in preclinical studies. However, its therapeutic potential and underlying molecular mechanisms in NSCLC remain uncharacterized. We evaluated the antiproliferative effects of GSK6853 on A549 and H1975 using CCK-8 and colony formation assays. Cell cycle distribution was analyzed by flow cytometry. Annexin V/PI method was performed to detect the rate of apoptosis. Transcriptomic changes induced by GSK6853 were assessed via RNA sequencing, followed by functional enrichment analysis and protein-protein interaction (PPI) network construction. Hub gene identification and pathway predictions were performed using bioinformatics tools. Western blotting was used to validate key protein expression changes. GSK6853 significantly inhibited the proliferation of A549 and H1975 cells in a dose-dependent manner and induced G0/G1 cell cycle arrest and apoptosis. RNA-seq analysis revealed that GSK6853 downregulated genes involved in DNA replication, homologous recombination, and base excision repair pathways. CCNA2 (Cyclin A2) emerged as a central hub gene among the downregulated targets. Western blotting confirmed that GSK6853 suppressed CCNA2 expression via inhibition of the JAK2/STAT3 signaling pathway. Clinical database analysis further showed that CCNA2 is highly expressed in LUAD tissues and its overexpression correlates with poor overall and disease-free survival. Our findings demonstrate that GSK6853 exerts potent antiproliferative effects in NSCLC by disrupting JAK2/STAT3 signaling pathway and suppressing CCNA2-mediated cell cycle progression, and further stimulates apoptosis. These results highlight GSK6853 as a promising therapeutic candidate for lung adenocarcinoma and support further preclinical and clinical evaluation.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1139-1147"},"PeriodicalIF":2.7,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12634795/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145400835","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The role of dinutuximab beta with beta cell function, apoptosis, and proliferation: new approaches to proteomic analysis of insulinoma.","authors":"Ayse Karatug Kacar","doi":"10.1007/s10637-025-01590-z","DOIUrl":"10.1007/s10637-025-01590-z","url":null,"abstract":"<p><p>The aim of this study was to investigate gene expressions related to beta cell function, and the altered protein profiles in insulinoma INS-1 cells following DB application, under both cytotoxic and non-cytotoxic conditions, with a focus on cell death and proliferation. Caspase 3 activity, LDH level, Bax, Bcl-2, PCNA, MafA, Nkx6.1, Pdx1, NeuroD1, and Pax6 gene expressions, TOS, TAS, and OSI were demonstrated. Protein profiles were analyzed using LC-MS/MS. The upstream and downstream proteins using the IPA database were determined. ERP29, UBE2V2, UBE2L6, PSMA4, TSMB10, ARF1, NUDCD2, ARF3, IRS1, PTEN, AKT, HSPA8, and Fibronectin levels were shown. The changes were observed in genes depending on pancreatic beta cell function and apoptosis. Bcl2, MafA, Nkx6.1, Pdx1, and NeuroD1 gene levels decreased, while Bax and Pax6 gene levels and TAS and TOS levels increased in the group given STZ + DB. PCNA, Bcl-2, Nkx6.1, Pdx1, and Pax6 gene levels increased, while MafA gene levels decreased in the group given DB. The protein ubiquitination pathway more predominates than the other many signaling pathways. Several proteins not previously associated, or only indirectly linked, with beta cell function, apoptosis, or proliferation were identified and characterized for the first time in insulinoma. These findings provide new insights and potential targets for the treatment of pancreatic cancer.</p>","PeriodicalId":14513,"journal":{"name":"Investigational New Drugs","volume":" ","pages":"1148-1165"},"PeriodicalIF":3.4,"publicationDate":"2025-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145345014","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}