Molecular Cancer Therapeutics最新文献

{"title":"Differential Sensitivity to xCT-inhibition by ME1 expression.","authors":"Katharine E Caldwell, Caitlyn B Brashears, Shub Mehta, John P Whelchel, David Barr, Jake P Roggin, Dirk Spitzer, Brian A Van Tine, William G Hawkins","doi":"10.1158/1535-7163.MCT-25-0299","DOIUrl":"10.1158/1535-7163.MCT-25-0299","url":null,"abstract":"<p><p>Many cancers overexpress malic enzyme 1 (ME1), an enzyme essential in redox homeostasis through the generation of cytoplasmic NADPH. While ME1 overexpression is correlated with aggressive cancer phenotypes, little is known about the metabolic consequences of ME1 absence, recently identified as characteristic of synovial sarcoma. ACXT-3102 is a novel, dual-domain therapeutic produced by the conjugation of erastin, a small molecule xCT-inhibitor, and sigma-2 ligand, shown to induce ROS-dependent cell death in various cancer models. This study examines ME1 absence as a marker of sensitivity to xCT-inhibition in multiple malignancies and its role as a potential therapeutic marker for ACXT-3102 treatment. ME1-expressing and non-expressing tumor cell lines were identified and matched ME1 knockdown (KD) and overexpressing (OE) lines were created. Sensitivity to ACXT-3102 treatment was investigated in various tumor lines in vitro and in vivo. ME1 absence is identified in a subset of multiple malignancies. ME1 KD increases ME1-expressing tumor cell sensitivity to ACXT-3102, while ME1 re-introduction decreases xCT-inhibition sensitivity in ME1-null lines in in vitro and in vivo models. Compared to ME1-expressing cancers, ME1 absence increases tumor sensitivity to xCT inhibition. Our findings suggest ME1-null and low-expressing tumors constitute a distinct subset across multiple solid tumor types, representing a potential metabolic vulnerability. Given this differential sensitivity, ME1 deficiency may serve as a promising biomarker for selecting patients likely to benefit from xCT-targeting therapies. These results support further investigation into ME1 expression as a predictive tool for clinical trial stratification and of xCT-inhibition treatment strategies.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13679071/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149025308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Systematic Evaluation of Combination Strategies with Rezatapopt in p53 Y220C-Mutant Cancer Models.","authors":"Tamer Ahmed, Erin E Michaud, Lizhong Xu, Hong Yang, Wenhui Li, Ling Lu, Mary Kate McBrayer, Yvonne Sun, Brandon M Russo, Chris L Mulligan, Josh Battaglia, Melissa L Dumble, Arnold J Levine, Anna M Puzio-Kuter, Masha V Poyurovsky","doi":"10.1158/1535-7163.MCT-26-0264","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0264","url":null,"abstract":"<p><p>Rezatapopt (PC14586), a first-in-class Y220C-selective p53 reactivator, demonstrates single-agent clinical efficacy; however, combinatorial strategies may enhance clinical outcomes. Here, we evaluated rezatapopt in combination with standard-of-care agents (chemotherapy and bevacizumab), murine double minute 2 (MDM2) inhibitors, and a library of FDA-approved compounds. While chemotherapy, bevacizumab, and MDM2 inhibitors showed in vivo efficacy, a high-throughput screen identified the phosphoinositide 3-kinase (PI3K)/ Protein Kinase B (AKT)/mechanistic target of rapamycin (mTOR) and mitogen-activated protein kinase pathways as top synergistic candidates. Validation confirmed that PI3Kα inhibition synergized with rezatapopt to deepen apoptosis and tumor growth inhibition in xenograft models. Thus, PI3K/mTOR pathway inhibition may represent a clinically actionable, conserved p53-reactivation vulnerability across diverse histologies harboring a TP53 Y220C mutation.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"149012661","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting the HEC1-NEK2 Axis Suppresses DLBCL Progression and Overcomes Vincristine Resistance.","authors":"Wenna Fu, Shaohua Xu, Zifan Cheng, Hongli Li, Yongtao Li, Hui Yang, Kaibo Zhu, Ganqian Zhu","doi":"10.1158/1535-7163.MCT-25-1503","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-25-1503","url":null,"abstract":"<p><p>Diffuse large B-cell lymphoma (DLBCL) is the most common and aggressive subtype of non-Hodgkin lymphoma (NHL), in which resistance to microtubule-targeting agents (MTAs) such as vincristine (VCR) remains a major therapeutic challenge. HEC1 (highly expressed in cancer 1) and NEK2 (NIMA-related kinase 2) are mitotic regulators that cooperate to maintain spindle integrity. Although HEC1 inhibitors that disrupt the HEC1-NEK2 interaction have been proposed as alternatives to MTAs with reduced neurotoxicity, their therapeutic relevance in DLBCL remains unknown. Here, we show that HEC1 and NEK2 are concomitantly upregulated in DLBCL, and their aberrant expression is associated with poor prognosis across multiple patient cohorts. The promoters of HEC1 and NEK2 show extensive sequence homology, and both genes are co-regulated by a shared transcriptional network including cell cycle-related transcription factors (TFs), involving FOXM1, MYC, and E2F family members, highlighting the central role of NEK2 in mitotic regulation together with the NDC80 complex. The HEC1 inhibitor TAI-1, which disrupts the HEC1-NEK2 interaction, induced degradation of HEC1 and NEK2, promoted GSK3β-dependent phosphorylation and degradation of β-catenin, and significantly suppressed DLBCL growth through mitotic catastrophe-associated apoptosis. Notably, HEC1 and NEK2 were upregulated in VCR-resistant DLBCL cells, and TAI-1 treatment restored VCR sensitivity and showed synergistic effects in combination with VCR. Our findings identify the HEC1-NEK2 axis as a therapeutic vulnerability in DLBCL and support combining HEC1 inhibitors with MTA-based chemotherapy to achieve superior anti-DLBCL efficacy.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148906744","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Targeting Compensatory AKT Activation Overcomes Resistance to AXL Inhibition in Acute Lymphoblastic Leukemia.","authors":"Haihong Gao, Yi Zhan, Miao Bao, Chuchu Liu, Tian Lan, Haidan Gao, Jianxin Xu","doi":"10.1158/1535-7163.MCT-26-0020","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0020","url":null,"abstract":"<p><p>The GAS6/AXL pathway plays a crucial role in promoting tumor survival and therapy resistance in various cancers. However, its significance in acute lymphoblastic leukemia (ALL) and the potential for its therapeutic targeting remain incompletely characterized. We integrated transcriptomic analysis of the public dataset GSE76349 with functional experiments in ALL cell lines. Cabozantinib was evaluated as an AXL inhibitor, and its effects on apoptosis, cell cycle, and signaling pathways were assessed using CCK-8 assays, RNA sequencing, Western blot, and flow cytometry. The functional role of AXL was confirmed via shRNA-mediated knockdown. The synergistic effect of combining cabozantinib with the AKT inhibitor capivasertib was evaluated in vitro and in a murine xenograft model. Bioinformatic analysis identified 8 key genes, including GAS6, associated with chemotherapy resistance. Cabozantinib exhibited strong cytotoxicity in AXL-high ALL cells, inducing apoptosis and G2/M arrest. Compensatory AKT activation was identified as a novel resistance mechanism in MOLT4 cells. AXL knockdown attenuated cabozantinib induced AKT suppression and apoptosis. Combined AXL and AKT inhibition synergistically enhanced anti leukemic effects in vitro and significantly reduced tumor burden in vivo with minimal toxicity. Our findings demonstrate that compensatory AKT activation limits the efficacy of cabozantinib in ALL and establish the combination of cabozantinib and capivasertib as a promising therapeutic strategy for refractory ALL.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900901","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Activation of PP2A-B56a leads to aberrant EGFR signaling and proliferative phenotypes in PDAC.","authors":"Claire M Pfeffer, Sydney J Clifford, Saadia A Karim, Ella Rose D Chianis, Brittany N Heil, Lauren E Gartenhaus, Emma F Kay, Garima Baral, Elizabeth G Hoffman, Sagar M Utturkar, Harish Kothandaraman, Whitney Smith-Kinnaman, Kasi Hansen, Emily G Smith, Elisabeth Porter, Fu-Ping Zhang, Nadia A Lanman, Jukka Westermarck, Emma H Doud, Amber L Mosley, Jennifer P Morton, Brittany L Allen-Petersen","doi":"10.1158/1535-7163.MCT-25-0970","DOIUrl":"10.1158/1535-7163.MCT-25-0970","url":null,"abstract":"<p><p>Pancreatic ductal adenocarcinoma (PDAC) stands to become the second most deadly cancer by 2030. Mutations in the small GTPase, KRAS, occur in over 90% of PDAC patients and drive signaling plasticity through phosphorylation cascades. Protein phosphatases are master regulators of signal transduction, yet the contribution of phosphatase dysregulation to mutant KRAS phenotypes is poorly understood. Protein phosphatase 2A (PP2A) inhibits KRAS effectors, placing this family of enzymes as key regulators of PDAC signaling. However, we previously demonstrated that pharmacological activation of PP2A elicits heterogeneous responses in PDAC cells, with some cell lines displaying augmented oncogenic signaling despite increased phosphatase activity. Here, we determined the impact of the specific PP2A subunit, B56a, on PDAC phenotypes using both genetic and pharmacological activation strategies in human PDAC cell lines and genetic mouse models. We demonstrate that B56a knockout reduces PDAC proliferation while exogenous expression exacerbates proliferative phenotypes. This increase in proliferation predominately occurs through epidermal growth factor receptor (EGFR), a critical signaling node associated with poor patient outcome. The activation of EGFR by PP2A-B56a is mediated through increased expression and processing of EGFR ligands, such as amphiregulin. In vivo, the genetic loss of Cip2a, an endogenous PP2A inhibitor, significantly increases EGFR activation and decreases overall survival. Finally, pharmacological activation of PP2A leads to increased EGFR signaling in tumors; however, EGFR inhibition mitigates this signaling and significantly decreases tumor growth compared to single-agent treatment alone. Together, these studies implicate a previously undescribed non-canonical role for PP2A-B56a in EGFR signaling that contributes to PDAC progression.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":""},"PeriodicalIF":6.9,"publicationDate":"2026-09-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148900905","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Antibody-Drug Conjugates Prepared with Peptide Asparaginyl Ligases Achieve Strong In Vitro and In Vivo Antitumor Activity.","authors":"Abbas El Sahili, Siew Pheng Lim, Seetharamsing Balamkundu, Srujana Kishore, Wei Min Chen, Fupeng Li, Keith Leong, Chuan Fa Liu, Julien Lescar","doi":"10.1158/1535-7163.MCT-25-0286","DOIUrl":"10.1158/1535-7163.MCT-25-0286","url":null,"abstract":"<p><p>Antibody-drug conjugates (ADC) are a rapidly expanding class of biopharmaceuticals for cancer-targeted therapy, with 15 ADCs approved for clinical use and more than a hundred candidates in clinical development. ADCs comprise a tumor-specific monoclonal antibody to which a cytotoxic payload is attached via a linker. Approved ADCs are heterogeneous products encompassing a range of drug-to-antibody ratios (DAR) due to the chemical methods employed for conjugation. Achieving precise DAR control is expected to improve product homogeneity, pharmacokinetics, safety, and clinical efficacy. In this study, we developed a rapid and efficient two-component bioconjugation system comprising a recombinant peptide asparaginyl ligase (PAL) and a human glutaminyl cyclase (hQC) to conjugate anti-HER2 antibodies. Trastuzumab and disitamab were conjugated with single or branched payloads, yielding ADCs with DAR values ranging from 2 to 8. These ADCs demonstrated cytotoxicity comparable with their chemically conjugated counterparts, trastuzumab deruxtecan (DXd, ENHERTU) and disitamab vedotin (Aidixi), against HER2-expressing breast cancer cell lines and Patient-Derived Xenograft (PDX) models. Notably, SGZ026, a PAL-conjugated trastuzumab DXd with a DAR of 3.9, exhibited better in vivo mouse plasma stability compared with ENHERTU (DAR 8). Despite carrying approximately half the cytotoxic payload per antibody, a single dose of SGZ026 effectively inhibited tumor growth in breast cancer PDX models with high or intermediate HER2 expression, achieving efficacy comparable with ENHERTU. These findings highlight a novel and robust enzyme-based conjugation technology for developing homogeneous ADCs with an improved therapeutic window.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1525-1536"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147521487","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"PRMT5 Inhibition by SCR-6920 Downregulates HIF-1α and Exhibits Synergistic Antitumor Activity with Bevacizumab in Ovarian Cancer.","authors":"Guimei Yang, Huixia Dou, Liting Xue, Weijie Chen, Yao Guo, Grace Xue, Ying Sun, Hanxiao Shi, Jian Li, Jianing Song, Zhen Li, Congjun Zhang, Renhong Tang, Feng Zhou","doi":"10.1158/1535-7163.MCT-25-1105","DOIUrl":"10.1158/1535-7163.MCT-25-1105","url":null,"abstract":"<p><p>Protein arginine methyltransferase 5 (PRMT5) is a critical therapeutic target in cancer. In this study, we report SCR-6920, a potent and selective oral PRMT5 inhibitor characterized by a substrate-competitive binding mode to PRMT5:methylosome protein 50 with high affinity. SCR-6920 shows broad antitumor activity in vitro and in vivo, along with favorable pharmacokinetics and tumor-biased distribution. Notably, RNA sequencing analysis links vascular endothelial growth factor (VEGF) to PRMT5, and further studies show that SCR-6920 downregulates hypoxia-inducible factor-1α (HIF-1α) through the ubiquitin-proteasome degradation pathway, thereby reducing downstream VEGF expression and secretion. Thus, PRMT5 inhibition enhances hypoxia-induced pathway disruption, and a further in vivo efficacy study demonstrates a synergistic effect for SCR-6920 combined with bevacizumab against ovarian cancer. Additionally, SCR-6920 improves the efficacy of clinical first-line ovarian cancer therapies (paclitaxel, docetaxel, doxorubicin, and olaparib). This study identifies a promising PRMT5 inhibitor with synergistic activity with bevacizumab and reveals its regulation of HIF-1α signaling, highlighting the therapeutic potential of PRMT5 inhibition in combination regimens for ovarian cancer.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1513-1524"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147776616","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Editor's Note: Enhancement of Nab-paclitaxel Antitumor Activity Through Addition of Multitargeting Antiangiogenic Agents in Experimental Pancreatic Cancer.","authors":"Niranjan Awasthi, Changhua Zhang, Anna M Schwarz, Stefan Hinz, Margaret A Schwarz, Roderich E Schwarz","doi":"10.1158/1535-7163.MCT-26-0733","DOIUrl":"https://doi.org/10.1158/1535-7163.MCT-26-0733","url":null,"abstract":"","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":"25 9","pages":"1578"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"148875258","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dynamic Switching of Apoptosis-Modulating Bim Heterodimers in Response to BH3 Mimetics in Xenograft Models of Hematologic Malignancies.","authors":"Jeevan Prasaad Govindharajulu, Sharon Fluss, Melinda G Hollingshead, William Gillette, Dominic Esposito, Dianne L Newton, Luke H Stockwin, Li Chen, Shahanawaz Jiwani, Kelly Dougherty, Omozusi Andrews, Barry C Johnson, Yvonne A Evrard, Ralph E Parchment, James H Doroshow, Apurva K Srivastava","doi":"10.1158/1535-7163.MCT-25-0855","DOIUrl":"10.1158/1535-7163.MCT-25-0855","url":null,"abstract":"<p><p>This study tested the hypothesis that tumor cells can evade apoptosis following BH3 mimetic treatment by utilizing alternative Bim-binding partners. Levels of Bim heterodimers with Mcl-1, Bcl-2, and Bcl-xL were measured in multiple hematologic cell line xenograft models (AMO-1, MV4-11, and RPMI-8226) following single-dose S63845 or venetoclax; Bak-Bax heterodimer and cleaved caspase-3 (cCasp3) levels were measured to demonstrate mitochondrial apoptosis. Antitumor efficacies of these agents were measured in vivo in mice bearing AMO-1 or MV4-11 xenografts and in vitro in patient-derived lymphoblastoid-like cells. The mechanism of the combination activity of the CDC-like kinase inhibitor cirtuvivint with venetoclax was determined in MV4-11 and KG-1a xenografts. S63845 decreased Mcl-1-Bim levels in AMO-1 and MV4-11 tumors by ∼90% while unexpectedly decreasing Bcl-2-Bim and increasing Bcl-xL-Bim levels. Venetoclax decreased Bcl-2-Bim levels while increasing Mcl-1-Bim and Bcl-xL-Bim levels in MV4-11 tumors. The S63845 + venetoclax combination decreased Mcl-1-Bim levels and demonstrated greater cell killing activity and pharmacodynamic effects than either single agent in multiple models, including patient-derived lymphoblastoid-like cells. Cirtuvivint decreased Mcl-1 and Bim levels, combining with venetoclax to induce significantly greater Bak-Bax and cCasp3 responses than either single agent and induce regression of MV4-11 xenograft tumors. Our results elucidate quantitative pharmacodynamics of S63845, venetoclax, and cirtuvivint, an agent that is currently being evaluated with venetoclax to treat acute myeloid leukemia (NCT06484062). Compensatory increases in off-target Bim heterodimer levels in response to either S63845 or venetoclax offer a possible mechanism of clinical drug resistance.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1537-1549"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13535319/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147499355","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"TNIK Overexpression Is Sufficient for Chemoradiation Resistance in Limited-Stage Small Cell Lung Cancer.","authors":"Dipanwita Dutta Chowdhury, Eddie L Imada, Nick Connis, Jinhee Chang, Aaron Chan, Hwai Wei Tseng, Audrey Lafargue, Francesca A Carrieri, Triet Nguyen, Danielle N Waters, Elan R Simms, Amol C Shetty, Yang Song, Muhammad Ajmal Khan, Mohammad Rezaee, Phuoc T Tran, Luigi Marchionni, Christine L Hann","doi":"10.1158/1535-7163.MCT-25-0529","DOIUrl":"10.1158/1535-7163.MCT-25-0529","url":null,"abstract":"<p><p>Small cell lung cancer (SCLC) is characterized by early metastasis, intrinsic chemoradiation resistance, and tumor recurrence. Besides the lack of potentially targetable oncogenic drivers, therapeutic advancements are also hindered by the scarcity of surgically resected tissue specimens ideal for profiling studies. We used patient-derived xenografts (PDX) to model SCLC chemoradiation resistance and identified chemoradiation resistance candidate genes using RNA sequencing. Additionally, we used human SCLC cell lines to confirm our in vivo results and delineate the underlying mechanism. Transcriptome profiling showed that the Traf2- and Nck-interacting kinase (TNIK) gene was consistently upregulated in an array of SCLC PDXs exposed to chemoradiation compared with monotherapy, which is consistent with previous observations of TNIK amplification in human samples. Genetic depletion (P < 0.01) or pharmacologic inhibition (P < 0.0001) of TNIK reduced in vitro clonogenic survival of TNIKhigh SCLC cells and promoted sensitivity to chemoradiation. In vivo, pharmacologic inhibition of TNIK enhanced chemoradiation sensitivity (P < 0.0001) of the H446 cell line-derived xenograft (CDX) in NOD-SCID mice. Furthermore, pharmacologic inhibition of TNIK in vivo demonstrated sensitivity (P < 0.0001) to chemoradiotherapy (CRT) in LX33 PDX. These results indicate that TNIK plays a role in conferring resistance to chemoradiation in SCLC cell lines and in vivo in SCLC CDX and PDX models. Delineating the mechanism behind radiosensitization suggested that TNIK inhibition may impair the DNA damage response in irradiated cells. Collectively, these findings suggest that TNIK may be a promising therapeutic target in limited-stage SCLC and support further investigation of TNIK inhibition in combination with standard CRT.</p>","PeriodicalId":18791,"journal":{"name":"Molecular Cancer Therapeutics","volume":" ","pages":"1550-1562"},"PeriodicalIF":6.9,"publicationDate":"2026-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC13339944/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147468637","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}