TY - JOUR
T1 - Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts
AU - Wei, Lei
AU - Chintala, Sreenivasulu
AU - Ciamporcero, Eric
AU - Ramakrishnan, Swathi
AU - Elbanna, May
AU - Wang, Jianmin
AU - Hu, Qiang
AU - Glenn, Sean T.
AU - Murakami, Mitsuko
AU - Liu, Lu
AU - Gomez, Eduardo Cortes
AU - Sun, Yuchen
AU - Conroy, Jacob
AU - Miles, Kiersten Marie
AU - Malathi, Kullappan
AU - Ramaiah, Sudha
AU - Anbarasu, Anand
AU - Woloszynska-Read, Anna
AU - Johnson, Candace S.
AU - Conroy, Jeffrey
AU - Liu, Song
AU - Morrison, Carl D.
AU - Pili, Roberto
PY - 2016
Y1 - 2016
N2 - 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.
AB - 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.
KW - Patient-derived xenograft
KW - PI3KCA
KW - Urothelial carcinoma
UR - http://www.scopus.com/inward/record.url?scp=84998827924&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84998827924&partnerID=8YFLogxK
U2 - 10.18632/oncotarget.13062
DO - 10.18632/oncotarget.13062
M3 - Article
C2 - 27823983
AN - SCOPUS:84998827924
SN - 1949-2553
VL - 7
SP - 76374
EP - 76389
JO - Oncotarget
JF - Oncotarget
IS - 47
ER -