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

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.