Priority Research Papers:
Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts
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Lei Wei1,*, Sreenivasulu Chintala2,5,7,*, Eric Ciamporcero2,*, Swathi Ramakrishnan2,5, May Elbanna2,7, Jianmin Wang1, Qiang Hu1, Sean T. Glenn3, Mitsuko Murakami4, Lu Liu4, Eduardo Cortes Gomez4, Yuchen Sun4, Jacob Conroy4, Kiersten Marie Miles4, Kullappan Malathi6, Sudha Ramaiah6, Anand Anbarasu6, Anna Woloszynska-Read2,5, Candace S. Johnson2,5, Jeffrey Conroy4, Song Liu1, Carl D. Morrison4 and Roberto Pili2,7
1 Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA
2 Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA
3 Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA
4 Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA
5 Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA
6 Medical & Biological Computing Laboratory, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, INDIA
7 Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA
* These authors have contributed equally to this work
Roberto Pili, email:
Keywords: urothelial carcinoma, patient-derived xenograft, PI3KCA
Received: October 15, 2016 Accepted: October 22, 2016 Published: November 03, 2016
Purpose: Effective systemic therapeutic options are limited for bladder cancer. In this preclinical study we tested whether bladder cancer gene alterations may be predictive of treatment response. Experimental design: We performed genomic profiling of two bladder cancer patient derived tumor xenografts (PDX). We optimized the exome sequence analysis method to overcome the mouse genome interference. Results: We identified a number of somatic mutations, mostly shared by the primary tumors and PDX. In particular, BLCAb001, which is less responsive to cisplatin than BLCAb002, carried non-sense mutations in several genes associated with cisplatin resistance, including MLH1, BRCA2, and CASP8. Furthermore, RNA-Seq analysis revealed the overexpression of cisplatin resistance associated genes such as SLC7A11, TLE4, and IL1A in BLCAb001. Two different PIK3CA mutations, E542K and E545K, were identified in BLCAb001 and BLCAb002, respectively. Thus, we tested whether the genomic profiling was predictive of response to a dual PI3K/mTOR targeting agent, LY3023414. Despite harboring similar PIK3CA mutations, BLCAb001 and BLCAb002 exhibited differential response, both in vitro and in vivo. Sustained target modulation was observed in the sensitive model BLCAb002 but not in BLCAb001, as well as decreased autophagy. Interestingly, computational modelling of mutant structures and affinity binding to PI3K revealed that E542K mutation was associated with weaker drug binding than E545K. Conclusions: Our results suggest that the presence of activating PIK3CA mutations may not necessarily predict in vivo treatment response to PI3K targeted therapies, while specific gene alterations may be predictive for cisplatin response in bladder cancer models and, potentially, in patients as well.
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