Clinical Cancer Research最新文献

{"title":"Large scale multi-omic analysis identifies anatomic differences and immunogenic potential in subtypes of leiomyosarcoma","authors":"Galina Lagos, Roman Groisberg, Andrew Elliott, Don S. Dizon, Andreas Seeber, Geoffrey Thomas. Gibney, Margaret von Mehren, Kenneth Cardona, Michael J. Demeure, Richard F. Riedel, Vaia Florou, Alexander J. Chou, Jaime F. Modiano, Abhijeet Kumar, Moh'd M. Khushman, Gina Z. D'Amato, Andrea P. Espejo Freire, Bradley DeNardo, Jonathan C. Trent","doi":"10.1158/1078-0432.ccr-24-2503","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2503","url":null,"abstract":"Purpose: Comprehensive molecular profiling was used to define the genomic and immune landscapes of leiomyosarcomas (LMS) by anatomic subtype, which have not been completely characterized. Design: 1115 LMS samples, categorized into uterine (uLMS), retroperitoneal (rpLMS), or other (oLMS), underwent DNA/RNA sequencing (Caris Life Sciences). Genomic/transcriptomic profiles were compared across subtypes. Immune profiling was compared to melanoma (n=1255), an immunogenic tumor. Insurance claims data were used to infer real-world outcomes with immune checkpoint inhibitors (ICI) in LMS. Results: uLMS (n=701) were molecularly distinct from rpLMS (n=166) and oLMS (n=248). RB1 mutations and MAP2K4 copy number amplification were more common in non-uLMS. MED12 mutations were almost exclusive to uLMS. Traditional ICI response biomarkers (i.e. PD-L1) didn’t vary by anatomic site. Non-uLMS demonstrated upregulated immune-related gene sets, including interferon and inflammatory response pathways, and higher immune cell infiltration, especially CD8+ T cells and B cells (>2-fold increase, p<0.0001). LMS had lower immune cell abundance and T-cell inflamed scores (TIS) compared to melanoma, though 11% of oLMS samples had high TIS scores. In a real-world cohort (n=138), 29% of LMS patients receiving ICI were treated >6 months, indicating potential clinical benefit. Conclusion: Comprehensive profiling suggested that uLMS represents a molecularly distinct disease from non-uLMS. While traditional ICI response biomarkers were similar across anatomic subtypes, uLMS were immune cold compared to non-uLMS. Signals for ICI responsiveness, such as high TIS and immune cell abundance, in some tumors suggest that further research into immunotherapies for LMS is warranted.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"69 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653416","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":"IDO Believe in Immunotherapy","authors":"Peter D. Zang, Tanya B. Dorff","doi":"10.1158/1078-0432.ccr-24-4264","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-4264","url":null,"abstract":"IDO1 is central to immune downregulation. A recent phase I/II study tested the IDO1 inhibitor linrodostat with nivolumab +/- ipilimumab in patients with advanced solid tumors. While efficacy was not augmented, correlative analyses identified TDO2 as a resistance mechanism; dual targeting may be necessary to realize improved response to PD-1 inhibition.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"90 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653421","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":"Clinical validity of repeated circulating tumor cell enumeration as an early treatment monitoring tool for metastatic breast cancer in the PREDICT global pooled analysis","authors":"Wolfgang Janni, Thomas W.P. Friedl, Tracy C. Yab, Francois-Clément Bidard, Massimo Cristofanilli, Daniel F. Hayes, Michail Ignatiadis, Meredith M. Regan, Catherine Alix-Panabieres, William E. Barlow, Carlos Caldas, Lisa A. Carey, Luc Dirix, Tanja Fehm, Jose A. Garcia-Saenz, Paola Gazzaniga, Daniele Generali, Lorenzo Gerratana, Rafael Gisbert-Criado, William Jacot, Zefei Jiang, Simon A. Joosse, Evi Lianidou, Rafael López López, Mark J.M. Magbanua, Luis Manso, Dimitris Mavroudis, Volkmar Müller, Elisabetta Munzone, Klaus Pantel, Jean-Yves Pierga, Brigitte Rack, Sabine Riethdorf, Hope S. Rugo, Kostandinos Sideras, Stefan Sleijfer, Jeffrey Smerage, Justin Stebbing, Leon W.M.M. Terstappen, Jose Vidal-Martínez, Markus Wallwiener, Karthik V. Giridhar, Minetta C. Liu","doi":"10.1158/1078-0432.ccr-24-3108","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3108","url":null,"abstract":"Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in metastatic breast cancer (MBC) patients focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental design: In total, 4436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch®; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥ 1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg), 325 (7.3%) and 1189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), while 2009 (45.3%) patients had at least one CTC at both time points (pos/pos). Median OS for the neg/neg, neg/pos, pos/neg and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P < 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared to CTC non-responders (pos/pos) (HR 0.48, 95% CI 0.44 – 0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥ 5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in MBC are urgently needed.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"92 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143653426","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 dose escalation and cohort expansion study of CB307, a trispecific Humabody® against PSMA, CD137, and albumin in patients with PSMA-positive solid tumors","authors":"Johann S. de Bono, Anja Williams, Ignacio Melero, Anuradha Jayaram, Jessica E. Hawley, Bernard Doger de Speville, Irene Moreno, Daniel Castellano, Òscar Reig, Daan G. Knapen, Georgia Anguera, Julia Martinez, Eelke Gort, Maja de Jonge, Jose Luis Alonso-Romero, Valentina Boni, Jose Luis Perez-Gracia, Alejandro Falcon, Derk Jan de Groot, Andrew J. Pierce, Andrew J. Leishman, Peter Lloyd, Phillip D. Bartlett, Philip Bland-Ward, Albert Chau, Minjung Song, Kevin Duffy, Kenji Hashimoto, Elisabeth de Vries","doi":"10.1158/1078-0432.ccr-24-3581","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-3581","url":null,"abstract":"Background:CB307 is a tri-specific variable heavy-chain antibody fragment against PSMA, CD137, and human serum albumin. It is designed to mitigate hepatotoxicity by activating T cells only in the PSMA-positive tumors and to increase drug half-life by albumin binding. This Phase I study investigated the safety and tolerability of CB307 as monotherapy or with pembrolizumab.Methods: Patients who were heavily pretreated with PSMA-positive solid tumors were enrolled in the dose-escalation phase of CB307 monotherapy. Additional safety and efficacy of CB307 were assessed in CB307 monotherapy expansion cohort and in combination with pembrolizumab.Results:CB307 was administered in 75 patients. CB307 was given Q1W as monotherapy (N = 50) or in combination with pembrolizumab (N = 25). Two dose-limiting toxicities (DLTs, grade 3 transient transaminitis) were observed. A total of three grade 3 transaminitis events (one in the monotherapy cohort and two in the combination cohort) were observed, and none involved bilirubin elevation. Durable RECIST responses were observed in two patients with mCRPC enrolled in 800 mg CB307 monotherapy and in one patient in the combination cohort (overall response rate: 11.1% and 7.1%, respectively). A disease control rate (DCR) of 50% was observed in patients enrolled in the 800 mg CB307 monotherapy cohort and 42.9% in the combination cohort. In a post-hoc analysis, the response was numerically better in patients who had not received chemotherapy in the 6 months prior to starting CB307 (ORR = 20%, DCR 60% vs. ORR 0%, DCR 37.5%). CB307 induces cytotoxic cell expansion in tumors and PD-L1 expression.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"10 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635277","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":"Mechanisms of Adaptive Resistance to Targeted Therapy in RET-Aberrant Cancers.","authors":"Sandra Ortiz-Cuaran, Camille Leonce","doi":"10.1158/1078-0432.CCR-24-3734","DOIUrl":"10.1158/1078-0432.CCR-24-3734","url":null,"abstract":"<p><p>The success of targeted therapies in oncogene-driven cancer is limited by adaptive or acquired treatment resistance, leading to disease progression. A recent study reports that YAP-dependent human epidermal growth factor receptor 3 (HER3) activation constitutes a therapeutic vulnerability of adaptive resistance to RET-targeted therapies in RET-altered cancers, highlighting a promising strategy to improve RET inhibitor tumor responses. See related article by Katayama et al., p. 1127.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"958-959"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142977815","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":"YAP Regulates HER3 Signaling-Driven Adaptive Resistance to RET Inhibitors in RET-Aberrant Cancers.","authors":"Yuki Katayama, Tadaaki Yamada, Keiko Tanimura, Hayato Kawachi, Masaki Ishida, Yohei Matsui, Soichi Hirai, Ryota Nakamura, Kenji Morimoto, Naoki Furuya, Sachiko Arai, Yasuhiro Goto, Yoshihiko Sakata, Kazumi Nishino, Michiko Tsuchiya, Akihiro Tamiya, Go Saito, Satoshi Muto, Takayuki Takeda, Koji Date, Yasuhito Fujisaka, Satoshi Watanabe, Daichi Fujimoto, Hisanori Uehara, Mano Horinaka, Toshiyuki Sakai, Seiji Yano, Shinsaku Tokuda, Koichi Takayama","doi":"10.1158/1078-0432.CCR-24-1762","DOIUrl":"10.1158/1078-0432.CCR-24-1762","url":null,"abstract":"<p><strong>Purpose: </strong>Rearranged during transfection (RET) aberrations represent a targetable oncogene in several tumor types, with RET inhibitors displaying marked efficacy. However, some patients with RET-aberrant cancer are insensitive to RET tyrosine kinase inhibitors (TKI). Recently, drug-tolerant mechanisms have attracted attention as targets for initial therapies to overcome drug resistance. The underlying mechanisms of drug-tolerant cell emergence treated with RET-TKIs derived from RET-aberrant cancer cells remain unknown. This study investigated the role of YAP-mediated HER3 signaling in the underlying mechanisms of adaptive resistance to RET-TKIs in RET-aberrant cancer cells.</p><p><strong>Experimental design: </strong>Four RET-aberrant cancer cell lines were used to assess sensitivity to the RET-TKIs selpercatinib and pralsetinib and to elucidate the molecular mechanisms underlying adaptive resistance using RNA sequencing, phospho-receptor tyrosine kinase antibody arrays, chromatin immunoprecipitation assay, and luciferase reporter assays. Clinical specimens from patients with RET fusion-positive lung cancer were analyzed for pretreatment YAP expression and correlated with treatment outcomes.</p><p><strong>Results: </strong>In high YAP-expressing RET-aberrant cancer cells, YAP-mediated HER3 signaling activation maintained cell survival and induced the emergence of cells tolerant to the RET-TKIs selpercatinib and pralsetinib. The pan-ErBB inhibitor afatinib and YAP/tea domain inhibitors verteporfin and K-975 sensitized YAP-expressing RET-aberrant cancer cells to the RET-TKIs selpercatinib and pralsetinib. Pretreatment YAP expression in clinical specimens obtained from patients with RET fusion-positive lung cancer was associated with poor RET-TKI treatment outcomes.</p><p><strong>Conclusions: </strong>The YAP-HER3 axis is crucial for the survival and adaptive resistance of high YAP-expressing RET-aberrant cancer cells treated with RET-TKIs. Combining YAP/HER3 inhibition with RET-TKIs represents a highly potent strategy for initial treatment. See related commentary by Ortiz-Cuaran and Leonce, p. 958.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1127-1141"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142567627","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":"Visualization of P2X7 Receptors in Living Human Gliomas: an 18F-GSK1482160 PET Imaging and Neuropatholopy Study","authors":"Weiyan Zhou, Qi Yue, Yifan Yuan, Qi Huang, Kun He, Tao Hua, Junbin Han, Yingfang He, Yihui Guan, Liang Chen, Fang Xie, Ying Mao","doi":"10.1158/1078-0432.ccr-24-2830","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2830","url":null,"abstract":"Purpose: PET imaging targeting the purinergic receptor subtype 7 (P2X7R) is of high interest for assessing glioma microenvironment. No reports were published regarding the P2X7R imaging in gliomas. Therefore, we compared the uptake characteristics of 18F-GSK1482160, a novel P2X7R ligand, to conventional 11C-MET PET and contrast-enhanced MRI in patients with gliomas. Experimental Design: Thirteen glioma patients (8 grade II, 5 grade III/IV) at initial diagnosis were consecutively included and underwent 18F-GSK1482160 PET, 11C-MET PET and MRI. The semi-quantitative analyses were performed in both 18F-GSK1482160 and 11C-MET PET images. Dynamic 18F-GSK1482160 PET analysis (n=8) generated parametric maps of binding potential (BPND) for the lesions. The tumor tissue was quantitatively assessed for P2X7R expression and infiltration of glioma associated microglia/macrophages (GAMs). Results: The multilinear reference tissue model (MRTM) was sufficient for quantifying 18F-GSK1482160. The SUVRmean for duration of 50-70min correlated best to mean BPND in the dynamic scan analysis. A strong linear relationship between the uptakes of 18F-GSK1482160 and 11C-MET was observed. The two tracers showed distinct spatial distribution by metabolic volume comparison, but were both associated with tumor grade and lesion contrast-enhancement status. IDH-wildtype gilomas tended to have higher tracer uptake for both tracers without reaching the level of significance. P2X7R in gliomas was expressed predominately by GAMs, and its expression exhibited positive correlation with uptake of 18F-GSK1482160 (r=0.7783, p=0.0029) in the tumors. Conclusions: The first-in-man study of P2X7R-PET demonstrated PET with 18F-GSK1482160 and 11C-MET provides complementary information characterizing tumor heterogeneity and the cellular composition of the microenvironment in untreated gliomas.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"90 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635147","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":"Enhancement of High-Dose Chemotherapy and Autologous SCT with the PARP Inhibitor Olaparib for Refractory Lymphoma.","authors":"Yago Nieto, Jeremy Ramdial, Benigno Valdez, Peter F Thall, Roland Bassett, Melissa Barnett, Samer Srour, Chitra Hosing, Amin Alousi, Muzaffar Qazilbash, Uday Popat, Alison Gulbis, Terri Lynn Shigle, Sairah Ahmed, Maria Guillermo Pacheco, Richard Champlin, Elizabeth J Shpall, Borje S Andersson","doi":"10.1158/1078-0432.CCR-24-3544","DOIUrl":"10.1158/1078-0432.CCR-24-3544","url":null,"abstract":"<p><strong>Purpose: </strong>More active high-dose chemotherapy (HDC) regimens are needed for autologous stem cell transplantation (ASCT) for refractory lymphomas. Seeking HDC enhancement with a PARP inhibitor, we observed marked synergy between olaparib and vorinostat/gemcitabine/busulfan/melphalan (GemBuMel) against lymphoma cell lines, mediated by the inhibition of DNA damage repair. Our preclinical work led us to clinically study olaparib/vorinostat/GemBuMel with ASCT.</p><p><strong>Patients and methods: </strong>Patients ages 15 to 65 years with refractory lymphoma and adequate end-organ function were eligible for this phase I trial. The olaparib dosage was escalated from 25 mg orally twice a day on days -11 to -3, plus vorinostat (1,000 mg orally/day, days -10 to -3), gemcitabine (2,475 mg/m2/day i.v., days -8 and -3), busulfan (target AUC 4,000 µmol/L.minute-1/day i.v., days -8 to -5), melphalan (60 mg/m2/day i.v., days -3 and -2), and rituximab (CD20+ tumors; 375 mg/m2, day -10), with ASCT.</p><p><strong>Results: </strong>Fifty patients were enrolled (23 with Hodgkin lymphoma, 18 with diffuse large B-cell lymphoma, and 9 with T-cell non-Hodgkin lymphoma); the median age was 35 years (range, 20-61); patients received a median of three prior lines of therapy (range, 2-7); 17 patients had previously relapsed after chimeric antigen receptor T-cell therapy or other cellular immunotherapies; 23 patients had PET-positive tumors at HDC (9 in progression). An olaparib dosage of 150 mg orally twice a day was identified as the recommended phase II dosage. The main extramedullary toxicity was mucositis. The overall response rate and complete response rate were 100% and 90%, respectively. At the median follow-up of 30 (range, 12-56) months, the event-free survival and overall survival rates were 72% and 82% in all patients and 71% and 88% in patients with prior CAR T-cell failure, respectively.</p><p><strong>Conclusions: </strong>In this first trial combining a PARP inhibitor with HDC, olaparib/vorinostat/GemBuMel was safe and showed promising activity in refractory lymphomas, including post-CAR-T relapses.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"975-982"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969824","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":"Impact of Co-mutations and Transcriptional Signatures in Non-Small Cell Lung Cancer Patients Treated with Adagrasib in the KRYSTAL-1 Trial.","authors":"Marcelo V Negrao, Alvaro G Paula, David Molkentine, Laura Hover, Monique Nilsson, Natalie Vokes, Lars Engstrom, Andrew Calinisan, David M Briere, Laura Waters, Jill Hallin, Lixia Diao, Mehmet Altan, George R Blumenschein, Ferdinandos Skoulidis, Jing Wang, Scott E Kopetz, David S Hong, Don L Gibbons, Peter Olson, James G Christensen, John V Heymach","doi":"10.1158/1078-0432.CCR-24-2310","DOIUrl":"10.1158/1078-0432.CCR-24-2310","url":null,"abstract":"<p><strong>Purpose: </strong>KRAS inhibitors are revolutionizing the treatment of non-small cell lung cancer (NSCLC), but clinico-genomic determinants of treatment efficacy warrant continued exploration.</p><p><strong>Experimental design: </strong>Patients with advanced KRASG12C-mutant NSCLC treated with adagrasib [KRYSTAL-1 (NCT03785249)] were included in the analysis. Pretreatment next-generation sequencing data were collected per protocol. HTG EdgeSeq Transcriptome Panel was used for gene expression profiling. Clinical endpoints included objective response, progression-free survival (PFS), and overall survival (OS). KRASG12C-mutant NSCLC cell lines and xenograft models were used for sensitivity analyses and combination drug screens.</p><p><strong>Results: </strong>KEAP1 MUT and STK11MUT were associated with shorter survival to adagrasib [KEAP1: PFS 4.1 vs. 9.9 months, HR 2.7, P < 0.01; OS 5.4 vs. 19.0 months, HR 3.6, P < 0.01; STK11: PFS 4.2 vs. 11.0 months, HR 2.2, P < 0.01; OS 9.8 months vs. not reached (NR), HR 2.6, P < 0.01]. KEAP1WT/STK11WT status identified adagrasib-treated patients with significantly longer PFS (16.9 months) and OS (NR). Preclinical analyses further validate the association between KEAP1 loss of function and adagrasib resistance. Adagrasib and mTOR inhibitor combinations produced higher treatment efficacy in NSCLC models harboring STK11 and KEAP1 co-mutations. NRF2HIGH signaling was associated with shorter survival to adagrasib (PFS: 4.2 vs. 8.4 months, HR 2.0, P = 0.02; OS: 6.5 vs. 19.0 months, HR 2.8, P < 0.01) even in patients with KEAP1WT NSCLC. KEAP1WT/STK11WT/NRF2LOW status identified patients-32%-with longer survival to adagrasib (PFS 12.0 vs. 4.2 months, HR 0.2, P < 0.01; OS NR vs. 8.0 months, HR 0.1, P < 0.01).</p><p><strong>Conclusions: </strong>KEAP1, STK11, and NRF2 status define patients with KRASG12C-mutant NSCLC with markedly distinct outcomes to adagrasib. These results further support the use of genomic features-mutational and nonmutational-for the treatment selection of patients with KRASG12C-mutant NSCLC.</p>","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":" ","pages":"1069-1081"},"PeriodicalIF":10.0,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11911804/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142969827","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The dynamically evolving cell states and ecosystem from benign nevi to melanoma","authors":"Xin Li, Xiyuan Zhang, Shuang Zhao, Shiyao Pei, Jie Sun, Liang Dong, Xu Pan, Wenhua Wang, Hao Liu, Yaoxuan Huang, Teng Liu, Jinhai Deng, Chunlan Hu, Chao Lv, Juan Su, Mingzhu Yin, Xiang Chen","doi":"10.1158/1078-0432.ccr-24-2971","DOIUrl":"https://doi.org/10.1158/1078-0432.ccr-24-2971","url":null,"abstract":"Purpose: Approximately 30% of non-chronically sun-damaged melanomas originate from nevi, yet the dynamic changes and crucial mechanisms driving the transition from benign nevi to melanoma remain elusive. Experimental Design: Here, we performed single-cell transcriptome sequencing on multiple paired tissue sites from 5 patients diagnosed with melanoma arising in congenital melanocytic nevi (CMN), identifying four distinct states of melanocyte subpopulations during the progression from nevi to melanoma, characterized by dynamic changes in their functions and regulatory pathways. Results: In the nevi state, interferon regulatory factor 1 (IRF1) was specifically upregulated in melanocytes, fibroblasts, and endothelial cells (ECs), potentially activating immune surveillance in the microenvironment. Conversely, the critical inhibitory checkpoint HLA-E for NK cells exhibited high expression in a cluster of malignant melanocytes and fibroblasts enriched in melanoma. This interaction with ligands expressed in NK cells could potentially serve as a key factor leading to immune evasion. In malignant melanoma samples, we detected high expression of Midkine (MDK) in melanocytes. It is a pivotal factor that facilitates melanoma invasion and malignant transformation, potentially through interaction with ECs to stimulate angiogenesis. The targets identified in our study are crucial factors in detecting the malignant transformation of nevi. Ultimately, we developed a malignant progression model capable of predicting patient prognosis and malignant progression status using bulk RNA sequencing (RNA-seq) data. Conclusions: Our study provides a high-resolution atlas of the malignant transformation of melanoma from nevi and highlights potential targets for further investigation.","PeriodicalId":10279,"journal":{"name":"Clinical Cancer Research","volume":"14 1","pages":""},"PeriodicalIF":11.5,"publicationDate":"2025-03-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143635280","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}