PO.CH02.01 · 化学

Proteomic analysis of BRAF-V600E mutant metastatic colorectal cancer FFPE tissues reveals potential involvement of WEE1 expression in therapeutic resistance

编号 7694 展板 18 时间 4/22 09:00–12:00 区域 Section 39 主讲 Shotaro Yamaguchi

分会场 Proteomics: Biomarker Discovery and Signaling Networks

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作者与单位

Shotaro Yamaguchi¹, Satoshi Muraoka², Yosui Nojima³, Toshiharu Hirose¹, Hidekazu Hirano¹, Natsuko Okita¹, Atsuo Takashima¹, Jun Adachi², Hirokazu Shoji¹, Ken Kato⁴

¹Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan,²Laboratory of Proteomics for Drug Discovery, Center for Drug Design Research, National Institute of Biomedical Innovation, Health and Nutrition, Osaka, Japan,³Center for Mathematical Modeling and Data Science, The University of Osaka, Osaka, Japan,⁴Head and Neck, Esophageal Medical Oncology / Department of Gastrointestinal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan

摘要 Abstract

Background and Aims: Approximately 10% of metastatic colorectal cancers (mCRC) harbor the BRAF -V600E mutation. Although targeted therapies such as encorafenib plus cetuximab with or without binimetinib (BEACON regimen) have been developed for this subtype, clinical outcomes remain poor, and overcoming therapeutic resistance represents a critical unmet need. To elucidate the molecular mechanisms underlying this resistance, we performed a proteomic analysis using formalin-fixed paraffin-embedded (FFPE) tissues obtained from patients with BRAF -V600E mutant mCRC. The aim of this study was to identify proteins potentially associated with resistance to BRAF -targeted therapy and to explore therapeutic targets for this population. Methods: FFPE tumor samples were collected from patients with BRAF -V600E mutant mCRC prior to any systemic treatment. Sections (5 µm thick) were mounted on PEN glass slides, and macro-dissected tumor areas (12-130 mm 2 per sample) were processed for protein extraction. Proteins were purified and digested using the Single-pot, solid-phase-enhanced sample preparation (SP3) protocol, followed by mass spectrometric analysis on an Orbitrap Exploris 480. Furthermore, we retrospectively analyzed clinical data from patients who received the BEACON regimen as second-line treatment for mCRC at our hospital between December 2020 and April 2024. Correlations between quantitative protein expression and clinical outcomes, including progression-free survival (PFS), were assessed using the log-rank test. Results: A total of 15 patients were included, and protein quantification was successfully achieved in samples of 12 patients. Across these samples, 9,078 proteins were quantitatively profiled, and correlations between protein expression and PFS were examined. The median PFS (mPFS) for patients who received the BEACON regimen as second-line therapy was 6.9 months (95% CI, 2.6-11.0). Among the quantified proteins, 13 proteins showed a negative correlation with PFS (correlation coefficient [r] < -0.8), with WEE1 demonstrating the strongest correlation (r = -0.94). In contrast, no significant correlation was observed between WEE1 expression and PFS during first-line treatment (r = -0.48). When patients were stratified by WEE1 expression levels for the second-line setting, the high-WEE1 group exhibited significantly shorter PFS than the low-WEE1 group (mPFS: 3.6 months vs 10.8 months [HR, 21.88, 95% CI, 3.84-124.6]; p = 0.0005). Conclusion: Our proteomic analysis identified WEE1 expression as a potential biomarker associated with poor clinical outcomes in patients with BRAF -V600E mutant mCRC treated with the BEACON regimen. These findings suggest a context-dependent resistance mechanism as a promising therapeutic target warranting further investigation in preclinical and clinical settings.

利益披露 Disclosure

S. Yamaguchi, None.. S. Muraoka, None.. Y. Nojima, None. T. Hirose, Bristol Myers Squibb ). ONO Pharmaceutical, CO. LTD. ). MSD ). TAIHO Pharmaceutical, CO. LTD. ). Astellas Pharma Inc. ). H. Hirano, Bristol Myers Squibb ), Other, Honoraria. Ono Pharmaceutical, CO. LTD Other, Honoraria. Novartis ), Other, Honoraria. Daiichi-Sankyo, CO. LTD ), Other, Honoraria. Taiho Pharmaceutical, CO. LTD ), Other, Honoraria. PPD ). Boehringer Ingelheim ). ALX Oncology ). BeiGene ). Amgen ). Seagen ). N. Okita, None. A. Takashima, MSD ). AstraZeneca plc ). Amgen ). Eisai, CO. LTD ). Bristol Myers Squibb ). Seagen Inc ). Ono Pharmaceutical, CO. LTD ). Eli Lilly Other, Honoraria. Taiho Pharmaceutical, CO. LTD Other, Honoraria. Chugai Pharmaceutical, CO. LTD Other, Honoraria. Takeda Pharmaceutical, CO.LTD Other, Honoraria. Merck Serono Other, Honoraria. J. Adachi, Proteobiologics Employment, Stock. ONO Pharmaceutical, CO. LTD ). Boelinger Ingelheim ). Mitsubishi Tanabe Pharma ). Takeda Pharma ). Stemrim ). Kirin Holdings ). AMED JP19ck0106465h0001 ). JP23ak0101203h0001 ). JSPS KAKENHI 20K17069, 20H03544 ). H. Shoji, MSD ). Astellas Pharma Inc ). AstraZeneca plc ). AbbVie Inc ). Taiho Pharmaceutical CO, LTD ). Daiichi Sankyo CO, LTD ). Ono Pharmaceutical CO, LTD ). Elevation Oncology Inc ). Chugai Pharmaceutical, CO, LTD ). Metagen Therapeutics Inc ). K. Kato, Bristol Myers Squibb ), Other, Honoraria. MSD ). BeiGene ). Roche ). AstraZeneca plc ). Bayer ). Ono Pharmaceutical, CO. LTD ), Other, Honoraria. Taiho pharmaceutical, CO. LTD Other, Honoraria. Chugai Pharmaceutical, CO. LTD ). Shionogi Inc ).

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