Intra-tumour molecular heterogeneity of clear cell renal cell carcinoma reveals the diversity of the response to targeted therapies using patient-derived xenograft models
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Baoan Hong1, Yong Yang2, Sheng Guo3, Shayiremu Duoerkun4, Xiaohu Deng5, Dawei Chen3, Shijun Yu3, Wubin Qian3, Qixiang Li3, Qing Li6, Kan Gong1 and Ning Zhang2
1Department of Urology, Peking University First Hospital, Institute of Urology, Peking University, Beijing, P.R. China
2Department of Urology, Beijing Cancer Hospital, Beijing Institute for Cancer Research, Beijing, P.R. China
3Division of Translational Oncology, Crown Bioscience, Taicang, Jiangsu, P.R. China
4Department of Urology, Central Hospital of HaMi Region, Xinjiang, P.R. China
5Department of Urology, People’s Hospital of Kelamayi, Xinjiang, P.R. China
6Center for Cellular & Structural Biology, School of Pharmaceutical Sciences, Sun Yat-Sen University, Guangzhou, P.R. China
Ning Zhang, email: [email protected]
Kan Gong, email: [email protected]
Keywords: clear cell renal cell carcinoma, molecular heterogeneity, targeted therapy, patient-derived xenograft model, precision medicine
Received: December 08, 2016 Accepted: April 26, 2017 Published: May 10, 2017
Inter- and intra-tumour molecular heterogeneity is increasingly recognized in clear cell renal cell carcinoma (ccRCC). It may partially explain the diversity of responses to targeted therapies and the various clinical outcomes. In this study, a 56-year-old male ccRCC patient with multiple metastases received radical nephrectomy and resection of the metastatic tumour in chest wall. The surgical specimens were implanted into nude mice to establish patient-derived xenograft (PDX) models with KI2367 model derived from the primary tumour and KI2368 model from the metastastic tumour. The two modles were treated with Sorafenib, Sunitinib, Axitinib, combined Sorafenib/Sunitinib, or alternating therapy of Sorafenib and Sunitinib. Significant anti-tumour activity was found in KI2367 treated with Sorafenib/Sunitinib monotherapy, combined Sorafenib/Sunitinib, and alternating therapy of Sorafenib/Sunitinib (P<0.05) but not in that treated with Axitinib monotherapy. In contrast, KI2368 was significantly responsive to Sunitinib monotherapy, combined Sorafenib/Sunitinib therapy and alternating therapy of Sorafenib/Sunitinib but not responsive to Sorafenib and Axitinib monotherapy (P<0.05). RNAseq of the two models demonstrated that the expression levels of 1,725 genes including the drug targeted genes of PDGFA, PDGFB and PDGFRA were >5-fold higher in KI2367 than in KI2368 and the expression levels of 994 genes were > 5-fold higher in KI2368 than in KI2367. These results suggest the presence of intra-tumour molecular heterogeneity in this patient. This heterogeneity may influence the response to targeted therapies. Multiple biopsy, liquid biopsy and genomic analysis of intra- tumour molecular heterogeneity may help guide a more precise and effective plan in selecting targeted therapies for ccRCC patients.
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