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

Hiroyuki 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 GoldbergMichael J Hall, Aaron James Scott, Jimmy J Hwang, Emil Lou, Benjamin A Weinberg, John Marshall, Sanjay Goel, Joanne Xiu, W Michael Korn, Alan P Venook, Yu Sunakawa, Heinz-Josef Lenz

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish
Article number113914
Pages (from-to)113914
JournalEuropean Journal of Cancer
Early online dateJan 10 2024
StatePublished - Apr 2024


  • Antineoplastic Combined Chemotherapy Protocols
  • Bevacizumab/therapeutic use
  • Cell Cycle Proteins/genetics
  • Cetuximab/therapeutic use
  • Chaperonins/genetics
  • Colonic Neoplasms
  • Colorectal Neoplasms/drug therapy
  • Gene Expression
  • Humans
  • Molecular Chaperones
  • Phenylurea Compounds
  • Pyridines
  • Rectal Neoplasms
  • Retrospective Studies


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