Clinical Cancer Research最新文献

{"title":"Clinical and Translational Results from PORTER, a Multi-cohort Phase 1 Platform Trial of Combination Immunotherapy in Metastatic Castration-Resistant Prostate Cancer.","authors":"Matthew D Galsky, Karen A Autio, Christopher R Cabanski, Kristopher Wentzel, Julie N Graff, Terence W Friedlander, Timothy R Howes, Kristin M Shotts, Julie Densmore, Marko Spasic, Diane M Da Silva, Richard O Chen, Jennifer Lata, Jeffrey Skolnik, Tibor Keler, Michael J Yellin, Theresa M LaVallee, Justin Fairchild, Silvia Boffo, Jill O'Donnell-Tormey, Ute Dugan, Nina Bhardwaj, Sumit K Subudhi, Lawrence Fong","doi":"10.1158/1078-0432.CCR-24-3693","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-3693","url":null,"abstract":"<p><strong>Purpose: </strong>Current immune checkpoint therapies offer limited benefits for metastatic castration-resistant prostate cancer (mCRPC). Novel combinations may enhance immunotherapy efficacy.</p><p><strong>Patients and methods: </strong>We conducted an open-label, non-comparative platform trial (NCT03835533) in mCRPC to assess nivolumab-based combinations. The cohorts were: A) bempegaldesleukin 0.006 mg/kg and nivolumab 360 mg intravenously Q3W, B) stereotactic body radiation therapy 30-50 Gray, CDX-301 75 μg/kg subcutaneously for 5 days, poly-ICLC 1 mg intramuscularly twice weekly for 3 weeks, and nivolumab 480 mg Q4W, and C) CDX-301 75 μg/kg for 10 days, INO-5151 3 mg intramuscularly on Lead-in Day 8, Day 1 of Cycles 1-3, then Q12W, and nivolumab 480 mg Q4W. The primary endpoint was safety; secondary endpoints included composite response rate (radiographic, PSA, or circulating tumor cell responses), 6-month disease control rate, progression-free survival, and overall survival. Serial blood and tissue samples were analyzed for pharmacodynamics and association with disease control.</p><p><strong>Results: </strong>43 patients enrolled (N = 14, 15, 14 in Cohorts A, B, C). Grade 3-4 treatment-related adverse events (TRAEs) occurred in 10 (71%), 2 (13%), and 2 (14%) patients, respectively, with one Grade 5 TRAE in Cohort A. Composite response rates were 7% (1/14), 33% (5/15), and 7% (1/14). Across cohorts, 6-month disease control was associated with pre-existing memory/regulatory T cells, TNFα, and other inflammatory pathways.</p><p><strong>Conclusions: </strong>Cohort B, which combined radiation therapy with CDX-301, poly-ICLC, and nivolumab, demonstrated encouraging clinical activity. Pre-existing rather than treatment-induced immune activation was associated with clinical benefit across cohorts, highlighting the importance of baseline immune fitness.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440021","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Increased interaction between B cells and CD3+ T cells in non-progressors with human papillomavirus-associated oropharyngeal squamous cell carcinoma.","authors":"Kathleen R Bartemes, Raymond M Moore, Brenna C Novotny, Kevin D Pavelko, Will A Sherman, Michael Rivera, Joaquin J Garcia, Linda X Yin, Daniel J Ma, Eric J Moore, Kathryn M Van Abel, David M Routman","doi":"10.1158/1078-0432.CCR-24-2425","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-2425","url":null,"abstract":"<p><strong>Background: </strong>Tumor-infiltrating lymphocytes (TILs) are associated with decreased risk of recurrence in human papillomavirus-associated oropharyngeal squamous cell carcinoma (HPV(+)OPSCC). The composition and spatial distribution of TILs and tumor-infiltrating immune cells is not well characterized.</p><p><strong>Methods: </strong>Formalin-fixed paraffin-embedded primary and lymph node (LN) tumor tissues from ten progressors (cases) and ten matched non-progressors (controls) were interrogated by imaging mass cytometry. Immune, stromal, and tumor cells were quantified from selected regions of interest (ROIs) using machine learning. Nearest neighbors, cell-cell interactions, and niche analyses were performed.</p><p><strong>Results: </strong>In primary ROIs, immune cell, lymphocyte, T cell, CD8+ T cell, and innate cell prevalence was significantly greater in controls. High prevalence of immune cells, lymphocytes, innate cells, and CD4+ T cells in primary tissues was significantly associated with increased time to event (TTE). Although primary and LN prevalence of T cells, CD4+ T cells, CD8+ T cells, macrophages, and tumor cells were significantly correlated, differences in LNs were neither significant nor associated with TTE. Average distances between T cells and nearest B cells, and between lymphocytes and nearest tumor cells were decreased in control primary tissues. Interactions between B cells and T cells were less organized in primary tissues from cases. A niche predominantly comprising lymphocytes was associated with longer TTE.</p><p><strong>Conclusion: </strong>In HPV(+)OPSCC, immune cell subset prevalence in primary tumors differs with outcome and is associated with TTE. Interactions between B cells and both T cell subsets are associated with longer TTE, underscoring the importance of active intratumoral immune responses in outcomes.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440043","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Biomarkers of radioresistance in head and neck cancer: a new beginning.","authors":"Yuan James Rao","doi":"10.1158/1078-0432.CCR-24-4223","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-24-4223","url":null,"abstract":"<p><p>The development of biomarkers of radioresistance in head and neck cancer may help personalize treatment. This commentary puts in context the findings of a secondary analysis of NRG/RTOG 9512, a trial of fractionation in T2N0 glottic cancer, which observed that NFE2L2/KEAP1/CUL3 mutations are correlated with local recurrence and disease-free survival.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":""},"PeriodicalIF":10.0,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143440018","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Correction: Targeting the Phosphoinositide 3-Kinase p110-α Isoform Impairs Cell Proliferation, Survival, and Tumor Growth in Small Cell Lung Cancer.","authors":"Anna Wojtalla, Barbara Fischer, Nataliya Kotelevets, Francesco A Mauri, Jens Sobek, Hubert Rehrauer, Carlos Wotzkow, Mario P Tschan, Michael J Seckl, Uwe Zangemeister-Wittke, Alexandre Arcaro","doi":"10.1158/1078-0432.CCR-25-0031","DOIUrl":"https://doi.org/10.1158/1078-0432.CCR-25-0031","url":null,"abstract":"","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"31 4","pages":"787"},"PeriodicalIF":10.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143432722","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Determinants of Response to Sequential Pembrolizumab with Trastuzumab Plus Platinum/5FU in HER2-positive Gastric Cancer: A Phase II Chemoimmunotherapy Trial","authors":"Sung Hee Lim, Minae An, Hyuk Lee, You Jeong Heo, Byung-Hoon Min, Arnav Mehta, Samuel Wright, Kyoung-Mee Kim, Seung Tae Kim, Samuel J. Klempner, Jeeyun Lee","doi":"10.1158/1078-0432.ccr-24-3528","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3528","url":null,"abstract":"Purpose: Adding pembrolizumab to first-line 5FU/platinum chemotherapy plus trastuzumab improves outcomes in advanced HER2+ gastroesophageal adenocarcinomas, but the benefit is largely confined to dual HER2+ and PD-L1+ patients. To assess the contributions of components, we conducted a phase II trial evaluating 5FU/platinum/trastuzumab and added pembrolizumab in cycle 2 in patients with metastatic HER2+ disease. Patients and Methods: Treatment naive advanced HER2+ gastroesophageal cancer patients underwent a baseline biopsy, and received a single dose of 5FU/platinum with trastuzumab followed by repeat biopsy. Pembrolizumab was added, and a third biopsy was performed after 6 cycles. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progression free (PFS), and overall survival. Exploratory biomarker analysis and dynamic changes in HER2 and PD-L1 were prespecified. Results: Sixteen patients were enrolled. The ORR was 69%, and the median PFS was 11.9 months. Serial whole-exome, single-cell RNA, T-cell receptor sequencing and spatial transcriptomics from pre-treatment and on-treatment samples revealed early trastuzumab-induced natural killer cell infiltration in HER2+ tumor beds and an increase in Fc receptor (FcR) gamma III expression in macrophages, suggesting that trastuzumab directs FcR-mediated antibody-dependent cytotoxicity. This favorable remodeling was enhanced by the addition of pembrolizumab, primarily in PD-L1+ samples. We observed TGF-β signaling in HER2-negative tumor regions, which was associated with non-responder status. Conclusions: These data highlight the biology of intratumoral heterogeneity, and the impact of tumor and immune cell features on clinical outcomes and may partly explain the lesser magnitude of pembrolizumab benefit in HER2+ and PD-L1 negative subgroups.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"64 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143435291","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Next-Generation Sequencing-Based MSI Scoring Predicts Benefit in Mismatch Repair-Deficient Tumors Treated with Nivolumab: Follow-up on NCI-MATCH Arm Z1D.","authors":"Jonathan D Schoenfeld, Nilofer S Azad, Jacob Gross, Li Chen, Michael J Overman, Katrina Kao, Latifa Jackson, Donna Brunnquell, Xiangning Bu, Christina Coppola, Ping Guan, Jennifer Lee, David Sims, Rebecca Fuchs, Jason L Weirather, Kathleen L Pfaff, Lauren Gunasti, Srin Ranasinghe, Stanley R Hamilton, Victoria Wang, Peter J O'Dwyer, Catherine J Wu, Scott J Rodig, David R Patton, Lyndsay Harris","doi":"10.1158/1078-0432.CCR-24-0427","DOIUrl":"10.1158/1078-0432.CCR-24-0427","url":null,"abstract":"<p><strong>Purpose: </strong>Mismatch repair-deficient (dMMR) tumors have demonstrated favorable responses to immune checkpoint inhibition targeting PD-1. However, more in-depth identification of predictors of response could further refine patient selection for immunotherapy treatment.</p><p><strong>Patients and methods: </strong>We undertook integrated evaluation performed on samples collected from 28 of 42 patients enrolled on the NCI-Molecular Analysis for Therapy Choice arm Z1D trial that evaluated PD-1 inhibition treatment with nivolumab in patients with noncolorectal dMMR tumors. Genomic analyses were performed using next-generation sequencing (NGS), whole-exome sequencing, and RNA sequencing and supplemented by multiplex immunofluorescence performed on tissue samples.</p><p><strong>Results: </strong>In this dMMR population, more extensive alterations of microsatellites as assessed by measures of NGS were associated with clinical benefit and tumor mutational burden. RNA sequencing further revealed associations between clinical benefit and immune infiltration index. Gene sets enriched in patients with clinical benefit included IFN signaling, antigen processing, and PI3K-AKT-mTOR signaling, whereas hedgehog signaling was found to be enriched in subjects lacking clinical benefit.</p><p><strong>Conclusions: </strong>These genomic data highlight the importance of immune infiltration and antigen presentation in dMMR tumors that respond to immune checkpoint blockade. In addition, they suggest that, even within a dMMR population, NGS-based measures of microsatellite instability could serve as biomarkers of immunotherapy response.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"667-677"},"PeriodicalIF":10.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142817441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Human Pancreatic Cancer Single-Cell Atlas Reveals Association of CXCL10+ Fibroblasts and Basal Subtype Tumor Cells.","authors":"Ian M Loveless, Samantha B Kemp, Kailee M Hartway, Jacob T Mitchell, Yuesong Wu, Samuel D Zwernik, Daniel James Salas-Escabillas, Sydney Brender, Madison George, Yetunde Makinwa, Thais Stockdale, Kendyll Gartrelle, Rohit G Reddy, Daniel W Long, Allison Wombwell, Julie M Clark, Albert M Levin, David Kwon, Ling Huang, Ralph Francescone, Débora B Vendramini-Costa, Ben Z Stanger, Adam Alessio, Andrew M Waters, Yuehua Cui, Elana J Fertig, Luciane T Kagohara, Brian Theisen, Howard C Crawford, Nina G Steele","doi":"10.1158/1078-0432.CCR-24-2183","DOIUrl":"10.1158/1078-0432.CCR-24-2183","url":null,"abstract":"<p><strong>Purpose: </strong>Pancreatic ductal adenocarcinoma (PDAC) patients with tumors enriched for the basal-like molecular subtype exhibit enhanced resistance to standard-of-care treatments and have significantly worse overall survival compared with patients with classic subtype-enriched tumors. It is important to develop genomic resources, enabling identification of novel putative targets in a statistically rigorous manner.</p><p><strong>Experimental design: </strong>We compiled a single-cell RNA sequencing (scRNA-seq) atlas of the human pancreas with 229 patient samples aggregated from publicly available raw data. We mapped cell type-specific scRNA-seq gene signatures in bulk RNA-seq (n = 744) and spatial transcriptomics (ST; n = 22) and performed validation using multiplex immunostaining.</p><p><strong>Results: </strong>Analysis of tumor cells from our scRNA-seq atlas revealed nine distinct populations, two of which aligned with the basal subtype, correlating with worse overall survival in bulk RNA-seq. Deconvolution identified one of the basal populations to be the predominant tumor subtype in nondissociated ST tissues and in vitro tumor cell and patient-derived organoid lines. We discovered a novel enrichment and spatial association of CXCL10+ cancer-associated fibroblasts with basal tumor cells. We identified that besides immune cells, ductal cells also express CXCR3, the receptor for CXCL10, suggesting a relationship between these cell types in the PDAC tumor microenvironment.</p><p><strong>Conclusions: </strong>We show that our scRNA-seq atlas (700,000 cells), integrated with ST data, has increased statistical power and is a powerful resource, allowing for expansion of current subtyping paradigms in PDAC. We uncovered a novel signaling niche marked by CXCL10+ cancer-associated fibroblasts and basal tumor cells that could be explored for future targeted therapies.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"756-772"},"PeriodicalIF":10.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142784327","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Bladder Preservation with Durvalumab plus Tremelimumab and Concurrent Radiotherapy in Patients with Localized Muscle-Invasive Bladder Cancer (IMMUNOPRESERVE): A Phase II Spanish Oncology GenitoUrinary Group Trial","authors":"Xavier Garcia-del-Muro, Begoña P. Valderrama, Ana Medina-Colmenero, Olatz Etxaniz, Regina Gironés Sarrió, María José Juan-Fita, Marcel Costa-García, Rafael Moreno, Isabel Miras Rodríguez, Irene Ortiz, Andrés Cuéllar, Ferran Ferrer, Francesc Vigués, Roberto de Haro Piedra, Arturo Candal Gomez, Salvador Villà, José Luis Pontones, Yasmina Murria, Guillermo Lendínez-Cano, Ramon Alemany","doi":"10.1158/1078-0432.ccr-24-2636","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2636","url":null,"abstract":"Purpose: The combination of radiation and immunotherapy potentiated antitumor activity in preclinical models. The purpose of this study is to explore the feasibility, safety, and efficacy of a bladder-preserving approach, including dual immune checkpoint blockade and radiotherapy, in patients with muscle-invasive bladder cancer (MIBC). Patients and Methods: Patients with localized MIBC underwent transurethral resection, followed by durvalumab (1,500 mg) plus tremelimumab (75 mg) every 4 weeks for three doses and concurrent radiotherapy (64–66 Gy to bladder). Patients with residual or relapsed MIBC underwent salvage cystectomy. The primary endpoint was complete response, defined as the absence of MIBC at posttreatment biopsy. Secondary endpoints were bladder-intact disease-free survival, distant metastasis–free survival, and overall survival. Results: Thirty-two patients were enrolled at six centers. Complete response was documented in 26 (81%) patients. Two patients had residual MIBC, and four patients were not evaluated. After a median follow-up of 27 months, 2 patients underwent salvage cystectomy. The 2-year rates for bladder-intact disease-free survival, distant metastasis–free survival, and overall survival were 65%, 83%, and 84%, respectively. The 2-year estimates of non–muscle-invasive bladder relapse, MIBC, and distant metastasis were 3%, 19%, and 16%, respectively. Grade 3 to 4 toxicities were reported in 31% of patients, with diarrhea (6%) and acute kidney failure (6%) being the most frequent. Conclusions: This multimodal approach including durvalumab plus tremelimumab with concurrent radiotherapy is feasible and safe, showing high efficacy in terms of response and eliciting bladder preservation in a large number of patients. Further research on this approach as an alternative to cystectomy is warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"28 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143426932","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A Phase I Study of FHD-609, a Heterobifunctional Degrader of Bromodomain-Containing Protein 9, in Patients with Advanced Synovial Sarcoma or SMARCB1-Deficient Tumors.","authors":"J Andrew Livingston, Jean-Yves Blay, Jonathan Trent, Claudia Valverde, Mark Agulnik, Mrinal Gounder, Axel Le Cesne, Meredith McKean, Michael J Wagner, Silvia Stacchiotti, Samuel Agresta, Alfonso Quintás-Cardama, Sarah A Reilly, Kathleen Healy, Denice Hickman, Tina Zhao, Alex Ballesteros-Perez, Alexis Khalil, Michael P Collins, Jessica Piel, Kim Horrigan, Ariel Lefkovith, Scott Innis, Alexander J Lazar, Gregory M Cote, Andrew J Wagner","doi":"10.1158/1078-0432.CCR-24-2583","DOIUrl":"10.1158/1078-0432.CCR-24-2583","url":null,"abstract":"<p><strong>Purpose: </strong>FHD-609, a potent, selective, heterobifunctional degrader of bromodomain-containing protein 9 (BRD9), was evaluated for treating patients with advanced synovial sarcoma or SMARCB1-deficient tumors.</p><p><strong>Patients and methods: </strong>In this multinational, open-label, phase I study (NCT04965753), patients received FHD-609 intravenously at escalating doses either twice weekly (5-80 mg; n = 40) or once weekly (40-120 mg; n = 15).</p><p><strong>Results: </strong>Fifty-five patients received FHD-609 for a median of 43 days. The maximum tolerated doses were 40 mg twice weekly and the equivalent weekly dose, 80 mg once weekly. Dose-limiting toxicities of QTc (heart rate-corrected QT interval) prolongation and syncope were observed at 40 and 60 mg twice weekly. Treatment-related adverse events were predominantly grades 1 to 2 in severity, most commonly dysgeusia (40%), dry mouth (29.1%), fatigue (27.3%), and anemia (25.5%). Eleven (20%) patients had treatment-emergent QTc (Fridericia formula) prolongation preceded by T-wave inversions; 21 (38.2%) patients had T-wave inversions without further cardiac events or ECG abnormalities. FHD-609 showed dose-dependent increases in pharmacokinetic exposure, with no substantial accumulation. Extensive BRD9 degradation in tumor tissue corresponded to the downregulation of cancer cell proliferation gene sets. One (2%) patient achieved a partial response; eight (15%) patients achieved stable disease, which lasted longer than 6 months in two patients.</p><p><strong>Conclusions: </strong>FHD-609 showed dose-dependent increases in systemic FHD-609 exposure and pharmacodynamic response profiles. The maximum tolerated doses were identified (40 mg twice weekly/80 mg once weekly) and preliminary clinical activity was observed. Future studies of BRD9 degraders will require strict cardiac monitoring given the QTc prolongation observed in this study.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"628-638"},"PeriodicalIF":10.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142806286","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Smoking-Associated Carcinogen-Induced Inflammation Promotes Lung Carcinogenesis via IRAK4 Activation.","authors":"Ritesh K Aggarwal, Simone Sidoli, Jingli Wang, Srabani Sahu, Rahul Sanawar, Varun Gupta, Srinivas Aluri, Vineeth Sukrithan, Charan T R Vegivinti, Phaedon D Zavras, Divij Verma, Shanisha Gordon-Mitchell, Beamon Agarwal, Tanya Verma, Daniel T Starczynowski, Ulrich G Steidl, Aditi Shastri, Balazs Halmos, Lindsay M LaFave, Haiying Cheng, Amit Verma, Yiyu Zou","doi":"10.1158/1078-0432.CCR-24-2182","DOIUrl":"10.1158/1078-0432.CCR-24-2182","url":null,"abstract":"<p><strong>Purpose: </strong>Even though smoking is associated with lung cancer, the exact molecular pathways that link carcinogens with inflammation and oncogenic transformation are not well elucidated. Two major carcinogens in cigarette smoke, nicotine-derived nitrosamine ketone, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), and benzo(α)pyrene (BaP), have not been tested in models that mimic inhaled exposure for prolonged periods of time.</p><p><strong>Experimental design: </strong>Mouse models were used for intratracheal delivery of NNK and BaP (NB) for 18 months. Tissue microarrays from human lung cancers were evaluated for IL-1 receptor-associated kinase-4 (IRAK4) expression. Functional effects of IRAK4 inhibition were evaluated in cell lines and xenografts.</p><p><strong>Results: </strong>Smoking-associated carcinogen-treated mice developed epithelial dysplasia followed by lung cancers at increased rates relative to controls. Histology revealed myeloid inflammation in murine lung tissues. Lung macrophages showed elevated levels of proinflammatory IL-1β when exposed to cigarette smoking condensate. A key downstream mediator of IL-1β signaling, IRAK4, was overexpressed in murine lung tissues exposed to carcinogens. The majority of human lung cancer samples also exhibited overactivated IRAK4 expression. IRAK4 localized in microtubules in lung cancer cell lines. Using mass spectrometry on isolated microtubules, we observed that IRAK4 inhibition was associated with decreased phosphorylation of tubular motility proteins, including myosin heavy-chain 9. Inhibition of IRAK4 resulted in decreased invasion in lung cancer cell lines and reduced growth of lung cancer xenografts.</p><p><strong>Conclusions: </strong>These data demonstrate that smoking-associated carcinogens can be linked to oncogenic transformation via inflammatory IRAK4 activation.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"746-755"},"PeriodicalIF":10.0,"publicationDate":"2025-02-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142863531","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}