The role of gene expression of CDC37 in colorectal cancer (CRC).

Abstract

237 Background: CDC37-HSP90 axis is an essential chaperoning system for stabilization of kinases. CDC37 determines selectivity of client kinases recognized by HSP90. We previously showed patients with CDC37-dependent ( CDC37 high expression) colorectal cancer (CRC) derived more benefit from regorafenib and bevacizumab both of which target HSP90 client kinases or signaling pathway, but not from cetuximab which targets HSP90 non-client kinase. However, molecular characteristics and interaction with relevant signaling pathways in CDC37-dependent CRC are largely unknown. Methods: We retrospectively reviewed CRC patient samples submitted to a commercial CLIA-certified laboratory (Caris Life Sciences, Phoenix AZ). Next-generation sequencing of DNA and RNA (whole-transcriptome sequencing) and immunohistochemistry were performed. Molecular profiles between top quartile transcripts per million for CDC37 expression (Q4, CDC37-high: n = 5056) and bottom quartile (Q1, CDC37-low: n = 5056) were compared for gene mutations, microsatellite instability (MSI) status, PD-L1 expression, co-expression of HSP90 genes ( HSP90AA1 and HSP90AB1), MAPK pathway activity score (MPAS), T-cell inflamed signature, and cell infiltration in the tumor microenvironment (TME) assessed by QuantiSEQ. Gene set enrichment analysis (GSEA) was performed between CDC37-high (Q4) and CDC37-low (Q1) tumors. Results: KRAS mutations trended higher in CDC37-high tumors compared to CDC37-low tumors (49.5% vs 47.1%) while APC (76.9% vs 72.3%), TP53 (75.5% vs 71.8%) and TCF7L2 (5.0% vs 3.5%) mutations were significantly higher in CDC37-high tumors compared to CDC37-low tumors (q < 0.05). No significance in expression quartiles were observed for dMMR/MSI-H or PD-L1 expression. HSP90AA1 and HSP90AB1 expression levels were significantly higher in CDC37-high tumors (2.9-fold and 2.6-fold in median, respectively; both q< 0.05). Both MPAS and T-cell inflamed signatures were significantly higher in CDC37-high tumors ( q< 0.05). Infiltration of NK cells, Tregs, neutrophils, M1 macrophages, and B-cells were greater in CDC37-high tumors (q < 0.05). GSEA showed several signaling pathways, such as KRAS, TGF-beta, hypoxia, WNT-beta catenin, and PI3K-AKT-MTOR, were enriched in CDC37-high tumors. Conclusions: Highly CDC37-expressed (CDC37-dependent) CRC was associated with aberrant TME where abundance of immune cell infiltrate and broad activation of kinase-related signaling pathways were evident. Our results support the kinase-stabilizing function of CDC37 in CRC. Further investigations combined with survival data are warranted to address the prognostic and predictive values of CDC37 expression in targeted therapies of CRC.