1. Predictive value of CDC37 gene expression for targeted therapy in metastatic colorectal cancer.
- Author
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Arai, Hiroyuki, Yang, Yan, Baca, Yasmine, Millstein, Joshua, Denda, Tadamichi, Ou, Fang-Shu, Innocenti, Federico, Takeda, Hiroyuki, Kubota, Yohei, Doi, Ayako, Horie, Yoshiki, Umemoto, Kumiko, Izawa, Naoki, Wang, Jingyuan, Battaglin, Francesca, Jayachandran, Priya, Algaze, Sandra, Soni, Shivani, Zhang, Wu, and Goldberg, Richard M.
- Subjects
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THERAPEUTIC use of antineoplastic agents , *VASCULAR endothelial growth factor antagonists , *THERAPEUTIC use of monoclonal antibodies , *PREDICTIVE tests , *PROTEIN kinase inhibitors , *BEVACIZUMAB , *GENETIC markers , *COLORECTAL cancer , *DESCRIPTIVE statistics , *RETROSPECTIVE studies , *TREATMENT effectiveness , *METASTASIS , *LONGITUDINAL method , *CANCER chemotherapy , *GENE expression profiling , *DRUG efficacy , *SURVIVAL analysis (Biometry) , *PROGRESSION-free survival , *CONFIDENCE intervals , *HYPOXEMIA - Abstract
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. • We explored a novel predictive biomarker CDC37 expression in treatment of mCRC. • CDC37 -highly expressed mCRC derived more benefit from bevacizumab and regorafenib. • No significant associations between CDC37 expression and cetuximab efficacy were observed. • The angiogenesis-relating pathways were activated in CDC37 -highly expressed CRC. [ABSTRACT FROM AUTHOR]
- Published
- 2024
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