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Cancer Cell International
Published in: Cancer Cell International 1/2020

Open Access 01-12-2020 | Kidney Cancer | Primary research

Association between copy-number alteration of +20q, −14q and −18p and cross-sensitivity to tyrosine kinase inhibitors in clear-cell renal cell carcinoma

Authors: Liang Wang, Yuqing Li, Yinfeng Lyu, Hui Wen, Chenchen Feng

Published in: Cancer Cell International | Issue 1/2020

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Abstract

Background

We aim to explore association between copy number alteration (CNA) and sensitivity to common tyrosine kinase inhibitors (TKIs) used in clear-cell renal cell carcinoma (ccRCC) treatment.

Methods

CNA with related sensitivity profiles were extracted from the Genomics of Drug Sensitivity in Cancer (GDSC) dataset and was cross-referenced with common CNA in ccRCC in the Cancer Genome Atlas (TCGA) dataset. Functional annotation was profiled using GSEA and NET-GE. Target genes within cytobands of interest were screened in silico and validated in vitro using proliferation assays in A498 and 786-O ccRCC cells.

Results

Four TKIs (Sunitinib, Cabozantinib, Axitinib and Sorafenib) that were clinically used in ccRCC were selected. In silico analysis showed gain of 20q (+20q) occurred in ~ 23% of cases and was associated with resistance to all four TKIs; loss of 14q (−14q) occurred in ~ 39% of cases and was associated with resistance to Sunitinib and Sorafenib; loss of 18p (−18p) occurred in ~ 39% of cases and was associated with sensitivity to Sunitinib and Sorafenib. All 3 CNAs were associated with worsened prognosis, respectively. Candidate target genes included of RBL1 on 20q, KLHL33 on 14q and ARHGAP28 on18q. In vitro validation showed RBL1 overexpression induced resistance to Sunitinib and Cabozantinib; KLHL33 silencing induced resistance to Sunitinib; ARHGAP28 silencing induced sensitivity to Cabozantinib. Functional annotation indicated FoxO signaling, hypoxic response and Wnt pathway, and Rho-related cellular adhesion were mechanistically associated with +20q, −14q and −18p, respectively.

Conclusion

Common CNAs in ccRCC are associated with cancer-intrinsic cross-sensitivity to common TKIs. Further validation and functional analyses are therefore needed.
Appendix
Available only for authorised users
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Metadata
Title
Association between copy-number alteration of +20q, −14q and −18p and cross-sensitivity to tyrosine kinase inhibitors in clear-cell renal cell carcinoma
Authors
Liang Wang
Yuqing Li
Yinfeng Lyu
Hui Wen
Chenchen Feng
Publication date
01-12-2020
Publisher
BioMed Central
Published in
Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI
https://doi.org/10.1186/s12935-020-01585-1

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