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Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer

结直肠癌 肿瘤科 医学 内科学 癌症研究 遗传增强 价值(数学) 癌症 基因 生物 遗传学 计算机科学 机器学习
作者
Hajime Arai,Yan Yang,Yasmine Baca,Joshua Millstein,Tadamichi Denda,Fang‐Shu Ou,Federico Innocenti,Hiroyuki Takeda,Yohei Kubota,Ayako Doi,Yoshiki Horie,Kumiko Umemoto,Naoki Izawa,Jingyuan Wang,Francesca Battaglin,Priya Jayachandran,Sandra Algaze,Shivani Soni,Wu Zhang,Richard M. Goldberg,Michael J. Hall,Aaron J. Scott,Jimmy J. Hwang,Emil Lou,Benjamin A. Weinberg,John L. Marshall,Sanjay Goel,Joanne Xiu,W. Michael Korn,Alan P. Venook,Yu Sunakawa,Heinz‐Josef Lenz
出处
期刊:European Journal of Cancer [Elsevier]
卷期号:: 113914-113914
标识
DOI:10.1016/j.ejca.2024.113914
摘要

Background CDC37 is a key determinant of client kinase recruitment to the HSP90 chaperoning system. We hypothesized that kinase-specific dependency on CDC37 alters the efficacy of targeted therapies for metastatic colorectal cancer (mCRC). Material and methods Two independent mCRC cohorts were analyzed to compare the survival outcomes between CDC37-high and CDC37-low patients (stratified by the median cutoff values): the CALGB/SWOG 80405 trial (226 and 207 patients receiving first-line bevacizumab- and cetuximab-containing chemotherapies, respectively) and Japanese retrospective (50 refractory patients receiving regorafenib) cohorts. A dataset of specimens submitted to a commercial CLIA-certified laboratory was utilized to characterize molecular profiles of CDC37-high (top quartile, N = 5055) and CDC37-low (bottom quartile, N = 5055) CRCs. Results In the bevacizumab-treated group, CDC37-high patients showed significantly better progression-free survival (PFS) (median 13.3 vs 9.6 months, hazard ratio [HR] 0.59, 95% confidence interval [CI] 0.44–0.79, p < 0.01) than CDC37-low patients. In the cetuximab-treated group, CDC37-high and CDC37-low patients had similar outcomes. In the regorafenib-treated group, CDC37-high patients showed significantly better overall survival (median 11.3 vs 6.0 months, HR 0.24, 95% CI 0.11–0.54, p < 0.01) and PFS (median 3.5 vs 1.9 months, HR 0.51, 95% CI 0.28–0.94, p = 0.03). Comprehensive molecular profiling revealed that CDC37-high CRCs were associated with higher VEGFA, FLT1, and KDR expressions and activated hypoxia signature. Conclusions CDC37-high mCRC patients derived more benefit from anti-VEGF therapies, including bevacizumab and regorafenib, but not from cetuximab. Molecular profiles suggested that such tumors were dependent on angiogenesis-relating pathways.
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