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. 2024 Apr:201:113914.
doi: 10.1016/j.ejca.2024.113914. Epub 2024 Feb 10.

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

Hiroyuki Arai  1 , Yan Yang  2 , Yasmine Baca  3 , Joshua Millstein  2 , Tadamichi Denda  4 , Fang-Shu Ou  5 , Federico Innocenti  6 , Hiroyuki Takeda  7 , Yohei Kubota  7 , Ayako Doi  7 , Yoshiki Horie  7 , Kumiko Umemoto  7 , Naoki Izawa  7 , Jingyuan Wang  8 , Francesca Battaglin  8 , Priya Jayachandran  8 , Sandra Algaze  8 , Shivani Soni  8 , Wu Zhang  8 , Richard M Goldberg  9 , Michael J Hall  10 , Aaron James Scott  11 , Jimmy J Hwang  12 , Emil Lou  13 , Benjamin A Weinberg  14 , John Marshall  14 , Sanjay Goel  15 , Joanne Xiu  3 , W Michael Korn  3 , Alan P Venook  16 , Yu Sunakawa  7 , Heinz-Josef Lenz  17
Affiliations

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

Hiroyuki Arai et al. Eur J Cancer. 2024 Apr.

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.

Keywords: CDC37; Chaperone; Colorectal cancer; HSP90; Targeted therapy.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: H-JL reports receiving honoraria from consultant/advisory board membership for Merck Serono, Bayer, and Genentech. EL reports research grants from the American Cancer Society (RSG-22–022-01-CDP) 2022–2026, and the Minnesota Ovarian Cancer Alliance in 2019, 2021, and 2022; The Randy Shaver Cancer Research and Community Fund; honoraria and travel expenses for lab-based research talks 2018–21, and equipment for laboratory-based research 2018-present, Novocure, Ltd; honorarium for panel discussion organized by Antidote Education for a CME module on diagnostics and treatment of HER2 + gastric and colorectal cancers, funded by Daiichi-Sankyo, 2021 (honorarium donated to lab); compensation for scientific review of proposed printed content, Elsevier Publishing and Johns Hopkins Press; consultant, Nomocan Pharmaceuticals (no financial compensation); Scientific Advisory Board Member, Minnetronix, LLC, 2018–2019 (no financial compensation); consultant and speaker honorarium, Boston Scientific US, 2019. Institutional Principal Investigator for clinical trials sponsored by Celgene, Novocure, Intima Biosciences, and the National Cancer Institute, and University of Minnesota membership in the Caris Life Sciences Precision Oncology Alliance (no financial compensation). YB, JX, and WMK are employees of Caris Life Sciences. All remaining authors have declared no conflicts of interest.

Figures

Figure 1.
Figure 1.
The Kaplan–Meier curves stratified by CDC37 expression using the median cutoff in patients treated with bevacizumab- or cetuximab-based first line chemotherapy (CALGB/SWOG 80405 trial cohort). (A) PFS in the bevacizumab arm. (B) OS in the bevacizumab arm. (C) PFS in the cetuximab arm. (D) OS in the cetuximab arm. Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
Figure 2.
Figure 2.
The Kaplan–Meier curves stratified by CDC37 expression in patients treated with regorafenib (Japanese retrospective cohort). (A) PFS. (B) OS. Abbreviations: CI, confidence interval; HR, hazard ratio; OS, overall survival; PFS, progression-free survival.
Figure 3.
Figure 3.
Comparison of the comprehensive molecular profiles between CDC37-high (Q4, CDC37-highest quartile) and CDC37-low (Q1, CDC37-lowest quartile) colorectal cancers in the Caris dataset. (A) Significant and trending gene mutations. (B) Frequency of PD-L1 positive and MSI-H/dMMR cases. (C) Co-expression with HSP90-encoding genes (HSP90AA1 and HSP90AB1). (D) Gene signature analyses including MPAS and T-cell inflamed signature. Abbreviations: dMMR, deficient mismatch repair; MPAS, MAPK pathway activity score; MSI-H, microsatellite instability-high.
See this image and copyright information in PMC

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