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

Lei Wei, Sreenivasulu Chintala, Eric Ciamporcero, Swathi Ramakrishnan, May Elbanna, Jianmin Wang, Qiang Hu, Sean T. Glenn, Mitsuko Murakami, Lu Liu, Eduardo Cortes Gomez, Yuchen Sun, Jacob Conroy, Kiersten Marie Miles, Kullappan Malathi, Sudha Ramaiah, Anand Anbarasu, Anna Woloszynska-Read, Candace S. Johnson, Jeffrey ConroySong Liu, Carl D. Morrison, Roberto Pili

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)76374-76389
Number of pages16
JournalOncotarget
Volume7
Issue number47
DOIs
StatePublished - 2016

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Phosphatidylinositol 3-Kinases
Heterografts
Urinary Bladder Neoplasms
Cisplatin
Mutation
Therapeutics
Genes
Exome
Neoplasms
Neoplasm Genes
Autophagy
Sequence Analysis
Research Design
Genome
RNA
Pharmaceutical Preparations

Keywords

  • Patient-derived xenograft
  • PI3KCA
  • Urothelial carcinoma

ASJC Scopus subject areas

  • Oncology

Cite this

Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts. / Wei, Lei; Chintala, Sreenivasulu; Ciamporcero, Eric; Ramakrishnan, Swathi; Elbanna, May; Wang, Jianmin; Hu, Qiang; Glenn, Sean T.; Murakami, Mitsuko; Liu, Lu; Gomez, Eduardo Cortes; Sun, Yuchen; Conroy, Jacob; Miles, Kiersten Marie; Malathi, Kullappan; Ramaiah, Sudha; Anbarasu, Anand; Woloszynska-Read, Anna; Johnson, Candace S.; Conroy, Jeffrey; Liu, Song; Morrison, Carl D.; Pili, Roberto.

In: Oncotarget, Vol. 7, No. 47, 2016, p. 76374-76389.

Research output: Contribution to journalArticle

Wei, L, Chintala, S, Ciamporcero, E, Ramakrishnan, S, Elbanna, M, Wang, J, Hu, Q, Glenn, ST, Murakami, M, Liu, L, Gomez, EC, Sun, Y, Conroy, J, Miles, KM, Malathi, K, Ramaiah, S, Anbarasu, A, Woloszynska-Read, A, Johnson, CS, Conroy, J, Liu, S, Morrison, CD & Pili, R 2016, 'Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts', Oncotarget, vol. 7, no. 47, pp. 76374-76389. https://doi.org/10.18632/oncotarget.13062
Wei, Lei ; Chintala, Sreenivasulu ; Ciamporcero, Eric ; Ramakrishnan, Swathi ; Elbanna, May ; Wang, Jianmin ; Hu, Qiang ; Glenn, Sean T. ; Murakami, Mitsuko ; Liu, Lu ; Gomez, Eduardo Cortes ; Sun, Yuchen ; Conroy, Jacob ; Miles, Kiersten Marie ; Malathi, Kullappan ; Ramaiah, Sudha ; Anbarasu, Anand ; Woloszynska-Read, Anna ; Johnson, Candace S. ; Conroy, Jeffrey ; Liu, Song ; Morrison, Carl D. ; Pili, Roberto. / Genomic profiling is predictive of response to cisplatin treatment but not to PI3K inhibition in bladder cancer patient-derived xenografts. In: Oncotarget. 2016 ; Vol. 7, No. 47. pp. 76374-76389.
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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

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KW - Urothelial carcinoma

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