Abstract
BackgroundWe 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.MethodsCNA 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.ResultsFour 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.ConclusionCommon CNAs in ccRCC are associated with cancer-intrinsic cross-sensitivity to common TKIs. Further validation and functional analyses are therefore needed.
Highlights
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 treatment
We have investigated associations between sensitivity to commonly used tyrosine kinase inhibitors (TKIs) and CNAs in clear-cell renal cell carcinoma (ccRCC) using an in silico exploration with in vitro validation
Higher expression of RBL1 was associated with significantly worsened prognosis in renal cell carcinoma (P = 2.5e-06) (Fig. 2h)
Summary
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. The IMDC risk group category reflects comprehensive survival data worldwide in the era of TKIs for metastatic renal cell carcinoma (mRCC) and in spite of newly emerging immune checkpoint inhibitors (ICIs) taking up frontlines of mRCC treatment, TKIs still play critical roles as TKI + ICI combo stands at the standard of care for mRCC as revealed by latest randomized trials [8,9,10,11]. Copy number alteration (CNA) plays critical role in carcinogenesis. Chromosome 14q loss is reported to define a molecular subtype of clear-cell renal cell carcinoma associated with poor prognosis [16]. There are only a handful of studies that link CNAs with treatment response in ccRCC
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