Division of Medical Oncology, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA; Department of Clinical Oncology, St. Marianna University School of Medicine, Kawasaki, Japan.
Department of Population and Public Health Sciences, Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.
Eur J Cancer. 2024 Apr;201:113914. doi: 10.1016/j.ejca.2024.113914. Epub 2024 Feb 10.
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).
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.
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.
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.
CDC37 是关键决定因素客户激酶募集到 HSP90 伴侣系统。我们假设激酶特异性依赖于 CDC37 改变了转移性结直肠癌 (mCRC) 的靶向治疗的疗效。
分析了两个独立的 mCRC 队列，以比较 CDC37-高和 CDC37-低患者的生存结果（按中位数分界值分层）：CALGB/SWOG 80405 试验（226 名和 207 名患者分别接受一线贝伐单抗和西妥昔单抗化疗）和日本回顾性（50 名接受regorafenib 的难治性患者）队列。利用提交给商业 CLIA 认证实验室的标本数据集，对 CDC37-高（四分位高位，N=5055）和 CDC37-低（四分位低位，N=5055）CRC 进行分子特征分析。
在贝伐单抗治疗组中，CDC37-高患者的无进展生存期（PFS）明显优于 CDC37-低患者（中位 PFS 13.3 个月 vs 9.6 个月，风险比[HR]0.59，95%置信区间[CI]0.44-0.79，p<0.01）。在西妥昔单抗治疗组中，CDC37-高和 CDC37-低患者的结局相似。在regorafenib 治疗组中，CDC37-高患者的总生存期（中位 PFS 11.3 个月 vs 6.0 个月，HR 0.24，95%CI 0.11-0.54，p<0.01）和 PFS（中位 PFS 3.5 个月 vs 1.9 个月，HR 0.51，95%CI 0.28-0.94，p=0.03）明显更好。综合分子特征分析表明，CDC37-高 CRC 与 VEGFA、FLT1 和 KDR 表达水平较高以及缺氧激活信号有关。
CDC37-高 mCRC 患者从抗 VEGF 治疗中获益更多，包括贝伐单抗和regorafenib，但从西妥昔单抗中获益较少。分子特征表明，这些肿瘤依赖于血管生成相关途径。
