Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts.
OBJECTIVE
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.


METHODS
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.
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Lei
L
Wei
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.|Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA.
Sreenivasulu
S
Chintala
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.
Eric
E
Ciamporcero
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Swathi
S
Ramakrishnan
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA.
May
M
Elbanna
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Jianmin
J
Wang
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Qiang
Q
Hu
Department of Cancer Genetics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Sean T
ST
Glenn
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Mitsuko
M
Murakami
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Lu
L
Liu
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Eduardo Cortes
EC
Gomez
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Yuchen
Y
Sun
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Jacob
J
Conroy
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Kiersten Marie
KM
Miles
Medical & Biological Computing Laboratory, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
Kullappan
K
Malathi
Medical & Biological Computing Laboratory, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
Sudha
S
Ramaiah
Medical & Biological Computing Laboratory, School of Biosciences and Technology, VIT University, Vellore, Tamil Nadu, India.
Anand
A
Anbarasu
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Anna
A
Woloszynska-Read
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Candace S
CS
Johnson
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Jeffrey
J
Conroy
Department of Biostatistics & Bioinformatics, Roswell Park Cancer Institute, Buffalo, NY, USA.
Song
S
Liu
Center for Personalized Medicine, Roswell Park Cancer Institute, Buffalo, NY, USA.
Carl D
CD
Morrison
Genitourinary Program, Roswell Park Cancer Institute, Buffalo, NY, USA.|Genitourinary Program, Indiana University-Simon Cancer Center, Indianapolis, IN, USA.
Roberto
R
Pili
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D004252:DNA Mutational Analysis; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D020869:Gene Expression Profiling; D023281:Genomics / Q000379:methods; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D009154:Mutation; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D015203:Reproducibility of Results; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D000073336:Whole Genome Sequencing; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D002945:Cisplatin; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human
PI3KCA; patient-derived xenograft; urothelial carcinoma