Abstract 785: Molecular profile of sunitinib resistance in clear-cell renal cell carcinoma
Authors: Torras Oscar Reig , Marin-Aguilera Mercedes , Jiménez Natalia , Laia Paré , Galvan Patricia , Mallofre Carme , Prat Aleix , Mellado Begoña 
Published: July 2017

Abstract
Background: Sunitinib (SU) is a tyrosine kinase inhibitor used in the first line setting in metastatic clear-cell renal cell carcinoma (ccRCC). Recently, nivolumab, a checkpoint inhibitor, has been approved as a second line therapy. The identification of biomarkers of resistance to these drugs may be useful to select patients’ treatment. In this study we investigated the molecular and immune profile associated to SU resistance.
Methods: Forty-four patients (pts) with metastatic ccRCC treated with SU were included. A global transcriptome analysis (Affymetrix Human Gene 2.0 ST array) on 6 extremely sensitive (ES; progression-free survival (PFS) &gt; 24 months) and 8 refractory (R; ; progression disease as best response) ccRCC pts treated with SU was performed. Differentially expressed genes were tested in the whole cohort by qPCR. In silico validation using the microarray data from 53 SU-treated pts (Beuselinck et al, Clin Cancer Res 2015) was performed. In addition 730 immune-related genes were tested in the same cohort and in 10 additional pts treated with anti-PD1/PD-L1 therapies as an exploratory analysis.
Results: Differential expression analysis between R and ES pts showed 330 differentially expressed genes: 148 were overexpressed and 182 underexpressed in R pts. Top two deregulated networks were centered in LYN and NR3C1 (Network 1), and in chemokine ligands and receptors (e.g. CCL5, CCRL1 and CXCL10) (Network 2). In Beuselinck dataset, 9 genes were differentially expressed between R and ES pts. The expression of 7 genes (BST2, CD44, ELK1, FADS2, LYN, NKAP and VEGFC) was correlated with a lower PFS in both cohorts (Table 1). A different immune-related molecular profile was shown between resistance to SU and to anti-PD1/PD-L1 therapies. TIM-3 was overexpressed in SU-sensitive pts and in anti-PD1/PD-L1 refractory pts.
Conclusions: We described a gene expression profile of SU resistance in ccRCC pts. The value of TIM-3 as a potential biomarker in ccRCC merits further exploration.
Survival analysis of selected genes in the training and validation set. *High vs low expression.HR (Training set)PMedian PFS, months*HR (Validation set)PMedian PFS, months*ELK12.66 (1.1 - 6.2)0.0225.2 vs 17.22.47 (1.2 - 5.1)0.01412 vs 24BST24.87 (1.5 - 15.7)0.0084.6 vs 10.62.22 (1.1 - 4.6)0.03111 vs 15CD442.55 (1.2 - 5.6)0.0235 vs 18.92.47 (1 - 6)0.0469 vs 14FADS22.84 (1.1 - 7.7)0.0394.2 vs 6.92.1 (1.1 - 4)0.02511 vs 19LYN5.38 (1.6 - 18.1)0.0064.5 vs 17.22.35 (1.1 - 4.9)0.0248.5 vs 16NKAP3 (1.3 - 7.1)0.0125.1 vs 17.22.27 (1.1 - 4.8)0.03111 vs 16VEGFC3.02 (1.2 - 7.5)0.0164.5 vs 17.21.97 (1 - 3.8)0.04512 vs 25
Citation Format: Oscar Reig Torras, Mercedes Marin-Aguilera, Natalia Jiménez, Paré Laia, Patricia Galvan, Carme Mallofre, Aleix Prat, Begoña Mellado. Molecular profile of sunitinib resistance in clear-cell renal cell carcinoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 785. doi:10.1158/1538-7445.AM2017-785