Predictive Value of CDC37 Gene Expression for Targeted Therapy in Metastatic Colorectal Cancer

Overview

Journal Eur J Cancer

Specialty Oncology

Date 2024 Feb 15

PMID 38359495

Authors

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 Goldberg

Michael 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

Affiliations

Soon will be listed here.

Abstract

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.

Citing Articles

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Lin F, Chen X, Liang C, Zhang R, Chen G, Zheng Z Front Pharmacol. 2025; 15:1477363.

PMID: 39744132 PMC: 11688280. DOI: 10.3389/fphar.2024.1477363.

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