Cancer Science最新文献

{"title":"Pyrotinib and Nab-Paclitaxel in HER2-Positive Breast Cancer (PANHER Trial): A Prospective, Single-Arm, Phase II Trial","authors":"Huan Li,&nbsp;Min Yan,&nbsp;Zhaohui Li,&nbsp;Xiujie Cui,&nbsp;Xuening Ji,&nbsp;Fengqi Fang,&nbsp;Yuyang Zhang,&nbsp;Yan Wang,&nbsp;Xiangyu Guo,&nbsp;Mingxi Jing,&nbsp;Zhichao Gao,&nbsp;Hui Cao,&nbsp;Fangyuan Dong,&nbsp;Jie Wu,&nbsp;Cui Jiang,&nbsp;Yangyang Duan,&nbsp;Xiaorui Li,&nbsp;Yujun Jiang,&nbsp;Lei Jiang,&nbsp;Ying E,&nbsp;Yufeng Jia,&nbsp;Liang Zhang,&nbsp;Pai Peng,&nbsp;Tao Sun","doi":"10.1111/cas.70086","DOIUrl":"10.1111/cas.70086","url":null,"abstract":"<p>Trastuzumab and pertuzumab combined with chemotherapy represent the standard therapy for first-line treatment of HER2-positive metastatic breast cancer (BC). Due to challenges related to availability and cost in China, it is necessary to explore treatments involving tyrosine kinase inhibitors (TKIs). In this multicenter, single-arm, open-label phase II trial, patients with HER2-positive BC were enrolled from seven hospitals in China. Patients received oral pyrotinib 400 mg once daily and intravenous nab-paclitaxel 125 mg/m² on days 1, 8, and 15 of each 28-day cycle until disease progression or intolerable toxicity. The primary endpoint was the objective response rate (ORR). Between December 2019 and December 2021, 51 patients were enrolled. Among all enrolled patients, 48 had at least one response evaluation. Of these evaluable patients, 39 patients achieved responses, resulting in a positive study outcome. The ORR was 76.5% (95% CI, 62.5%–87.2%), and the disease control rate was 94.1% (95% CI, 83.8–98.8). As of January 24, 2024, the median follow-up duration was 29.2 months (IQR, 24.9–33.2). The median progression-free survival was 14.6 months (95% CI, 8.0–24.2), and the median overall survival was not reached. Forty-nine patients (96.1%) developed grade ≥ 3 adverse events (AEs). The most common grade ≥ 3 AEs were decreased neutrophil count (43.1%), decreased white blood cell count (43.1%), and diarrhea (23.5%). Pyrotinib combined with nab-paclitaxel demonstrated promising efficacy for HER2-positive advanced breast cancer, with an acceptable safety profile.</p><p><b>Trial Registration:</b> chictr.org, ChiCTR1900023653</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1920-1929"},"PeriodicalIF":4.5,"publicationDate":"2025-04-22","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70086","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144053577","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":"In Vivo Reprogramming Highlights Epigenetic Regulation That Shapes Cancer Hallmarks","authors":"Yosuke Yamada,&nbsp;Nao Sankoda,&nbsp;Yasuhiro Yamada","doi":"10.1111/cas.70067","DOIUrl":"10.1111/cas.70067","url":null,"abstract":"<p>Douglas Hanahan added “non-mutational epigenetic reprogramming” and “unlocking phenotypic plasticity” as new hallmarks of cancer, proposing that cancer cells possess fundamental features that are not directly linked to their genetic abnormalities. In vivo reprogramming studies have demonstrated that non-mutational epigenetic regulation can cause cellular reprogramming, leading to cancer development at the organismal level. Given that epigenetic regulation functions as an interface between the cellular environment and gene expression, these results suggest that intercellular communications in the tumor microenvironment play a critical role in cancer development. This review first introduces genetic aberrations that cause cancer development. Then, it illustrates the impact of epigenetic abnormalities in cancer, especially with reference to studies that use in vivo reprogramming technologies. Finally, it discusses the importance of histological evaluations of tumor tissue to understand non-cell-autonomous epigenetic regulation that establishes cancer hallmarks.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1807-1814"},"PeriodicalIF":4.5,"publicationDate":"2025-04-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144035935","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":"Impact of Vitamin C on Immune Response and Edema Following Near-Infrared Photoimmunotherapy (NIR-PIT)","authors":"Hiroshi Yamamoto,&nbsp;Aki Furusawa,&nbsp;Hiroshi Fukushima,&nbsp;Seiichiro Takao,&nbsp;Motofumi Suzuki,&nbsp;Makoto Kano,&nbsp;Miyu Kano,&nbsp;Shuhei Okuyama,&nbsp;Ko Kitamura,&nbsp;Peter L. Choyke,&nbsp;Hisataka Kobayashi","doi":"10.1111/cas.70070","DOIUrl":"10.1111/cas.70070","url":null,"abstract":"<p>Near-infrared photoimmunotherapy (NIR-PIT) is a recently approved cancer therapy utilizing an antibody conjugated to IR700 dye which is injected and then followed with focal NIR light. NIR-PIT is ideal for focal therapy of cancer because of its cell specificity and minimal invasiveness compared to surgical resection. Most treatment-emergent adverse events are low grade and include edema, fatigue, and pain. However, edema in specific anatomic locations could lead to significant complications, such as airway obstruction, and thus, it is desirable to reduce edema if possible. Edema and the resulting pain are likely precipitated by reactive oxygen species generated primarily from the interaction of laser light with unbound antibody–photoabsorber conjugate. These reactive species can be neutralized by reducing agents, such as vitamin C, a potent reducing agent and proton donor. Based on its photochemical mechanisms, we hypothesized that pretreating patients with L-sodium ascorbate (L-NaAA) will reduce NIR-PIT-induced edema. Here, we evaluated the effect of L-NaAA concentration on edema as well as its effect on the immune responses after NIR-PIT. L-NaAA demonstrated concentration-dependent inhibition of edema after NIR-PIT without compromising the efficacy of NIR-PIT. Furthermore, L-NaAA did not impede the anticancer immune activation elicited by NIR-PIT, nor did it affect the efficacy of Treg-targeted NIR-PIT. NIR-PIT groups, both with and without L-NaAA, significantly inhibited tumor growth and resulted in markedly prolonged survival compared to the control group, but those with L-NaAA had reduced edema. Thus, L-NaAA may serve as a useful adjunct to NIR-PIT, enhancing its safety profile without detracting from its therapeutic efficacy.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1836-1846"},"PeriodicalIF":4.5,"publicationDate":"2025-04-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70070","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144026597","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":"p53 Deficiency in Colon Cancer Cells Promotes Tumor Progression Through the Modulation of Meflin in Fibroblasts","authors":"Eiji Kimura,&nbsp;Yoshito Hayashi,&nbsp;Kentaro Nakagawa,&nbsp;Hirotsugu Saiki,&nbsp;Minoru Kato,&nbsp;Ryotaro Uema,&nbsp;Takanori Inoue,&nbsp;Takeo Yoshihara,&nbsp;Akihiko Sakatani,&nbsp;Hiromu Fukuda,&nbsp;Ayaka Tajiri,&nbsp;Yujiro Adachi,&nbsp;Kazuhiro Murai,&nbsp;Shunsuke Yoshii,&nbsp;Yoshiki Tsujii,&nbsp;Shinichiro Shinzaki,&nbsp;Hideki Iijima,&nbsp;Tetsuo Takehara","doi":"10.1111/cas.70026","DOIUrl":"10.1111/cas.70026","url":null,"abstract":"<p>Cancer-associated fibroblasts (CAFs), a major component of the tumor microenvironment, play an important role in tumor progression. Colon cancer cells deficient in p53 activate fibroblasts and enhance fibroblast-mediated tumor growth. Meflin is a CAF marker capable of inhibiting tumor growth. In this study, we investigated the role of Meflin in fibroblasts using human cell lines (colon cancer HCT116 and fibroblasts CCD-18Co) and clinical specimens. TP53-suppressed HCT116 (HCT116^{<i>sh p53</i>}) cells cocultured with CCD-18Co cells showed significantly faster proliferation than HCT116^{<i>sh control</i>} cells. In xenograft experiments, the volume of tumors induced by coinoculation with HCT116^{<i>sh p53</i>} and CCD-18Co cells was significantly larger than that induced by HCT116^{<i>sh control</i>} cells co-inoculated with CCD-18Co cells. HCT116^{<i>sh p53</i>} cells increased the levels of CAF-like phenotypic markers in CCD-18Co cells. Moreover, Meflin expression was significantly reduced in CCD-18Co cells cocultured with HCT116^{<i>sh p53</i>} cells compared to that in CCD-18Co cells cocultured with HCT116^{<i>sh control</i>} cells. si-RNA-mediated inhibition of Meflin activated CCD-18Co cells into tumor-promoting CAF-like cells, which significantly promoted xenograft tumor growth. Overexpression of Meflin in CCD-18Co cells using lentivirus suppressed fibroblast-mediated growth of HCT116^{<i>sh p53</i>} tumor xenografts. The expression of Meflin in CCD-18Co cells was suppressed by TGF-β and enhanced by vitamin D. These results indicate that colon cancer cells deficient in p53 suppress Meflin expression in fibroblasts, which affects tumor growth by altering the properties of tumor growth-promoting CAFs. Our results suggest that targeting Meflin in fibroblasts may be a novel therapeutic strategy for colorectal cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1871-1882"},"PeriodicalIF":4.5,"publicationDate":"2025-04-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70026","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144057949","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":"Steroid-Modulated Transcription Synergistically Forms DNA Double-Strand Breaks With Topoisomerase II Inhibitor","authors":"Ying Zhao,&nbsp;Tetsuro Hisayoshi,&nbsp;Doudou Zhang,&nbsp;Saaya Suzuki,&nbsp;Takashi Watanabe,&nbsp;Atsuo Kobayashi,&nbsp;Qianqian Guo,&nbsp;Yukihide Momozawa,&nbsp;Takashi Shimokawa,&nbsp;Shunsuke Kato,&nbsp;Yoshio Miki,&nbsp;Shigeaki Sunada","doi":"10.1111/cas.70081","DOIUrl":"10.1111/cas.70081","url":null,"abstract":"<p>The synergistic effects of drug combinations have emerged as a promising approach for achieving efficient cancer treatment. Through our exploration of drug combinations, we found that medroxyprogesterone acetate (MPA), a steroid, induced a synergistic antitumor effect in combination with the topoisomerase II inhibitor etoposide (ETP). In this study, we investigated the mechanisms underlying this synergistic effect for potential clinical applications. To elucidate the relevant mechanisms, we performed a cell viability assay, cell cycle analysis, DNA repair assays, detection of DNA double-strand breaks (DSBs) and the nuclear localization of topoisomerase II (Top2), and genome-wide detection of DSBs. MPA synergistically increased ETP-induced DSBs, resulting in cell cycle arrest in the G2/M phase. Interestingly, this effect was not due to the inhibition of DSB repair but to a specific increase in the Top2-DNA covalent complex formed by ETP. A genome-wide search for DSB locations revealed that DSB formation was promoted near promoter regions, suggesting the involvement of MPA transcriptional modulation in this mechanism. We also found that various steroids promoted DSB formation when combined with ETP, strongly supporting our synergistic model. Therefore, this synergistic effect is based on an innovative mechanism that differs from conventional strategies targeting the DNA damage response and is expected to contribute toward novel therapeutic options.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1952-1962"},"PeriodicalIF":4.5,"publicationDate":"2025-04-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70081","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144039968","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":"Permeable Lung Vasculature Creates Chemoresistant Endothelial Niche by Producing SERPINE1 at Breast Cancer Metastatic Sites","authors":"Tsunaki Hongu,&nbsp; Sarenqiqige,&nbsp; Shandan,&nbsp;Hirokazu Kusunoki,&nbsp;Akihiko Ishimura,&nbsp;Takeshi Suzuki,&nbsp;Thordur Oskarsson,&nbsp;Noriko Gotoh","doi":"10.1111/cas.70050","DOIUrl":"10.1111/cas.70050","url":null,"abstract":"<p>Chemotherapy resistance remains a major obstacle for eradicating metastatic cancer cells in distant organs. We identified that endothelial cells (ECs) in the lungs, where breast cancer cells often metastasize, form a chemoresistant perivascular niche for disseminated breast cancer cells. By investigating the lung EC secretome activated by metastasis, we found that serine protease inhibitor family E member 1 (SERPINE1), encoded by <i>Serpine1</i>, is upregulated in metastasis-associated lung ECs. This upregulation shields cancer cells from paclitaxel-induced apoptosis and promotes cancer stem cell properties. <i>Serpine1</i> expression appears to be driven by YAP-TEAD activation in lung ECs that lose cell–cell contact, a phenomenon associated with increased vascular permeability in lungs affected by metastasis. Crucially, pharmacological inhibition of SERPINE1 enhances the chemotherapy sensitivity of metastatic breast cancer cells in the lung. Overall, our findings underscore the pivotal role of the vascular niche, which produces SERPINE1, in conferring chemoresistance to breast cancer cells during metastatic progression in the lungs.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 6","pages":"1604-1615"},"PeriodicalIF":4.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70050","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144041247","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":"Association of Intratumoral Bacterial Abundance With Lung Cancer Prognosis in Chiba University Hospital Cohort","authors":"Takahiro Ochi,&nbsp;Ryoji Fujiki,&nbsp;Masaki Fukuyo,&nbsp;Bahityar Rahmutulla,&nbsp;Takuya Nakagawa,&nbsp;Masayuki Ota,&nbsp;Jun-ichiro Ikeda,&nbsp;Yukiko Matsui,&nbsp;Ichiro Yoshino,&nbsp;Hidemi Suzuki,&nbsp;Atsushi Kaneda","doi":"10.1111/cas.70080","DOIUrl":"10.1111/cas.70080","url":null,"abstract":"<p>The relationship between cancer prognosis and intratumoral microbiome has recently gained attention. Regarding lung cancer, most studies have focused on bacteria outside tumors, such as sputum or lavage fluid, with few examining intratumoral bacteria and their impact on prognosis. In this study, we extracted DNA from lung tumor samples of 507 patients undergoing surgery at Chiba University Hospital and quantified intratumoral bacterial abundance using bacteria-specific PCR primers. Bacteria were detected in 77.1% of cases, and bacterial abundance was significantly higher in lung adenocarcinoma than in squamous cell carcinoma. Patients were categorized into three groups (High, Low, and Very-Low) based on bacterial abundance, and associations with clinicopathological factors were analyzed. In lung squamous cell carcinoma, higher bacterial abundance was significantly associated with worse recurrent-free survival and overall survival and was found to be a poor prognostic factor independent of pathological tumor stage. In conclusion, intratumoral bacterial abundance was found in the majority of lung cancer tissues, with variations based on pathology. This abundance may serve as a useful marker for stratifying lung squamous cell carcinoma with distinct prognoses.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"2040-2046"},"PeriodicalIF":4.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70080","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144043328","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":"First-Line Genomic Profiling in Previously Untreated Advanced Solid Tumors: 1-Year Follow-Up of the FIRST-Dx Study","authors":"Junichi Matsubara,&nbsp;Kumi Mukai,&nbsp;Tomohiro Kondo,&nbsp;Masahiro Yoshioka,&nbsp;Hidenori Kage,&nbsp;Katsutoshi Oda,&nbsp;Sadakatsu Ikeda,&nbsp;Hiromichi Ebi,&nbsp;Kei Muro,&nbsp;Shinya Kajiura,&nbsp;Ryuji Hayashi,&nbsp;Reiko Ashida,&nbsp;Masayuki Kitano,&nbsp;Manabu Muto","doi":"10.1111/cas.70077","DOIUrl":"10.1111/cas.70077","url":null,"abstract":"<p>The FIRST-Dx study prospectively evaluated the clinical utility of the comprehensive genomic profiling (CGP) test (FoundationOne CDx) in the first-line setting for patients with chemotherapy-naïve advanced solid tumors (gastrointestinal, biliary, pancreatic, lung, breast, gynecologic, melanoma) in six hospitals in Japan. Here, we report the results of the 1-year interim analysis of the follow-up study about the clinical benefits provided by the upfront CGP test. The primary endpoint was overall survival (OS), and secondary endpoints were the proportion of patients who actually received molecular-based recommended therapy (MBRT) determined by the molecular tumor board, best overall response rate (ORR) in each line of therapy, and progression-free survival (PFS) ratio (PFS on MBRT/PFS on the first-line therapy). Data from 172 patients with a median follow-up of 15.1 months (range: 0.1–21.5 months) were available. The median OS was not reached. Thirty-nine patients (22.7%) received MBRT during this follow-up period. ORR in first-line therapy was 56.3% in the MBRT group (<i>n</i> = 16) vs. 42.3% in the non-MBRT group (<i>n</i> = 137), and in the second-line was 26.3% in the MBRT group (<i>n</i> = 19) vs. 17.1% in the non-MBRT group (<i>n</i> = 82). Regarding the PFS ratio of second-line MBRT (<i>n</i> = 12), the median PFS ratio was 1.1, and four patients (33.3%) had a ratio ≥ 1.3, indicating that MBRT might be effective in changing the clinical outcome. The findings of this study imply that CGP testing before the standard of care for patients with advanced solid tumors could prove to be a clinically beneficial strategy for guiding subsequent precision anticancer treatments.</p><p><b>Trial Registration:</b> Japan Registry of Clinical Trials (jRCT) ID: jRCT1050220041</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1908-1919"},"PeriodicalIF":4.5,"publicationDate":"2025-04-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70077","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"144056520","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":"Novel TEAD1 Inhibitor VT103 Enhances Dabrafenib Efficacy in BRAF V600E Mutated Lung Adenocarcinoma via Survivin Downregulation","authors":"Kazutaka Hosoya,&nbsp;Hiroaki Ozasa,&nbsp;Hironori Yoshida,&nbsp;Hitomi Ajimizu,&nbsp;Takahiro Tsuji,&nbsp;Masatoshi Yamazoe,&nbsp;Tatsuya Ogimoto,&nbsp;Kentaro Hashimoto,&nbsp;Tomoko Funazo (Yamamoto),&nbsp;Keiichiro Suminaga,&nbsp;Yusuke Shima,&nbsp;Hiroshi Yoshida,&nbsp;Takashi Nomizo,&nbsp;Hiroaki Ito,&nbsp;Kazuhiro Terada,&nbsp;Shigeto Nishikawa,&nbsp;Toshi Menju,&nbsp;Akihiko Yoshizawa,&nbsp;Hiroshi Date,&nbsp;Toyohiro Hirai","doi":"10.1111/cas.70075","DOIUrl":"10.1111/cas.70075","url":null,"abstract":"<p>The <i>BRAF</i> V600E mutation is observed in 2% of the patients with lung adenocarcinoma (LUAD), and combination therapy targeting BRAF and mitogen-activated protein kinase (MEK) is the standard treatment for this population. However, acquired resistance inevitably develops, which highlights the need for novel therapeutic strategies. In this study, we established a patient-derived <i>BRAF</i> V600E-mutated LUAD cell line, KTOR81, and investigated the potential of targeting the Yes-associated protein 1 (YAP1)/transcriptional enhanced associate domain 1 (TEAD1) pathway in combination with BRAF inhibition. We observed that the novel TEAD1 inhibitor VT103 enhanced the efficacy of the BRAF inhibitor dabrafenib in KTOR81 cells and xenograft models. The combination of dabrafenib and VT103 downregulated the expression of the antiapoptotic protein survivin, which is transcriptionally regulated by the YAP1/TEAD1 complex, leading to increased apoptosis. Moreover, we used a LUAD tissue microarray to compare the staining patterns of YAP1, TEAD1, and survivin, and examined their association with prognosis. These analyses revealed a strong correlation between YAP1, TEAD1, and survivin expression in LUAD, suggesting the relevance of the YAP1/TEAD1-survivin axis beyond <i>BRAF</i> V600E-mutated cases. While no statistically significant association was observed between survivin expression and prognosis, when limited to driver oncogene-positive patients, high survivin expression was suggested to be associated with poor prognosis. These findings provide preclinical evidence for the efficacy of combining TEAD1 inhibition with BRAF-targeted therapy in BRAF V600E-mutated LUAD and highlight the YAP1/TEAD1-survivin axis as a potential therapeutic target especially in the driver oncogene-positive LUAD patients.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1883-1896"},"PeriodicalIF":4.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70075","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812759","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":"BRCA1 Promoter Methylation in Ovarian Cancer: Clinical Relevance and a Novel Diagnostic Approach Using Fragment Analysis","authors":"Saki Tsuchimochi,&nbsp;Yoko Yamamoto,&nbsp;Ayumi Taguchi,&nbsp;Masahito Kawazu,&nbsp;Kenbun Sone,&nbsp;Masako Ikemura,&nbsp;Kana Tamai,&nbsp;Shuhei Kitamura,&nbsp;Daisuke Yoshimoto,&nbsp;Sayuri Fukaya,&nbsp;Aya Ishizaka,&nbsp;Anh Duong Quynh,&nbsp;Akira Nishijima,&nbsp;Yuichiro Miyamoto,&nbsp;Mayuyo Mori,&nbsp;Osamu Hiraike,&nbsp;Kosei Hasegawa,&nbsp;Tetsuo Ushiku,&nbsp;Katsutoshi Oda,&nbsp;Yasushi Hirota,&nbsp;Yutaka Osuga","doi":"10.1111/cas.70078","DOIUrl":"10.1111/cas.70078","url":null,"abstract":"<p>Homologous recombination deficiency (HRD) tests, including MyChoice CDx, are companion diagnostics for poly (ADP-ribose) polymerase (PARP) inhibitors. <i>BRCA1</i> promoter hypermethylation, a major HRD cause, may correlate with poorer prognosis. This study aimed to develop a simple, accurate method for detecting <i>BRCA1</i> promoter hypermethylation and elucidate the characteristics of such cases. <i>BRCA1</i> promoter methylation was analyzed using bisulfite sequencing (BIS-seq) in high-grade serous ovarian carcinoma specimens. We developed a newly developed <i>BRCA1</i> methylation assay, <i>BRCA1</i>-Fragment Analysis of Methylation (<i>BRCA1</i>-FAM), which combines restriction enzyme digestion with fragment analysis. The accuracy of this assay was compared to the results of BIS-seq. We evaluated the relationship between <i>BRCA1</i> promoter hypermethylation and prognosis and examined its association with <i>BRCA1</i> expression and loss of heterozygosity. <i>BRCA1</i> mutations and promoter methylation were mutually exclusive in the analyzed cases, with methylation observed in 28.9% (22/76) of primary debulking surgery cases. The <i>BRCA1</i>-FAM showed high sensitivity (91.3%) and specificity (100%) for detecting <i>BRCA1</i> promoter hypermethylation, comparable to BIS-seq. Cases with <i>BRCA1</i> promoter hypermethylation had significantly poorer progression-free survival (log-rank test, <i>p</i> = 0.048). Among these cases, 86.4% displayed abnormal <i>BRCA1</i> immunostaining, with lower frequencies of <i>BRCA1</i> loss of heterozygosity compared to those of other groups. <i>BRCA1</i> promoter hypermethylation is associated with poor prognosis, underscoring the importance of its identification for HRD stratification. <i>BRCA1</i>-FAM is a simple and highly accurate method for evaluating <i>BRCA1</i> promoter methylation. This approach may potentially enhance the precision of personalized therapies for ovarian cancer.</p>","PeriodicalId":9580,"journal":{"name":"Cancer Science","volume":"116 7","pages":"1996-2007"},"PeriodicalIF":4.5,"publicationDate":"2025-04-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1111/cas.70078","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143812758","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}