A Functional Genetic Screen Identifies the Phosphoinositide 3-kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma
Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A c...
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| Vydané v: | European urology Ročník 71; číslo 6; s. 858 - 862 |
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Switzerland
Elsevier B.V
01.06.2017
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| Abstract | Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes.
Fibroblast growth factor receptor (FGFR) inhibitors are tested in bladder cancer patients. A genetic screen identified the phosphoinositide 3-kinase pathway to determine drug resistance. Combined treatment with FGFR and phosphoinositide 3-kinase inhibitors may improve response rates in patients with cancers harboring activating FGFR mutations |
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| AbstractList | Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes.Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes. Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes. Fibroblast growth factor receptor (FGFR) inhibitors are tested in bladder cancer patients. A genetic screen identified the phosphoinositide 3-kinase pathway to determine drug resistance. Combined treatment with FGFR and phosphoinositide 3-kinase inhibitors may improve response rates in patients with cancers harboring activating FGFR mutations Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 (FGFR3-TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes. Abstract Activating mutations and translocations of the FGFR3 gene are commonly seen in urothelial cell carcinoma (UCC) of the bladder and urinary tract. Several fibroblast growth factor receptor (FGFR) inhibitors are currently in clinical development and response rates appear promising for advanced UCC. A common problem with targeted therapeutics is intrinsic or acquired resistance of the cancer cells. To find potential drug targets that can act synergistically with FGFR inhibition, we performed a synthetic lethality screen for the FGFR inhibitor AZD4547 using a short hairpin RNA library targeting the human kinome in the UCC cell line RT112 ( FGFR3 - TACC3 translocation). We identified multiple members of the phosphoinositide 3-kinase (PI3K) pathway and found that inhibition of PIK3CA acts synergistically with FGFR inhibitors. The PI3K inhibitor BKM120 acted synergistically with inhibition of FGFR in multiple UCC and lung cancer cell lines having FGFR mutations. Consistently, we observed an elevated PI3K-protein kinase B pathway activity resulting from epidermal growth factor receptor or Erb-B2 receptor tyrosine kinase 3 reactivation caused by FGFR inhibition as the underlying molecular mechanism of the synergy. Our data show that feedback pathways activated by FGFR inhibition converge on the PI3K pathway. These findings provide a strong rationale to test FGFR inhibitors in combination with PI3K inhibitors in cancers harboring genetic activation of FGFR genes. |
| Author | Halonen, Pasi van der Heijden, Michiel S. Beijersbergen, Roderick L. van den Heuvel, Michel M. Šuštić, Tonći Wang, Liqin Leite de Oliveira, Rodrigo Lieftink, Cor van de Ven, Marieke Bernards, René |
| Author_xml | – sequence: 1 givenname: Liqin surname: Wang fullname: Wang, Liqin organization: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 2 givenname: Tonći surname: Šuštić fullname: Šuštić, Tonći organization: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 3 givenname: Rodrigo surname: Leite de Oliveira fullname: Leite de Oliveira, Rodrigo organization: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 4 givenname: Cor surname: Lieftink fullname: Lieftink, Cor organization: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 5 givenname: Pasi surname: Halonen fullname: Halonen, Pasi organization: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 6 givenname: Marieke surname: van de Ven fullname: van de Ven, Marieke organization: Mouse Clinic Intervention Unit, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 7 givenname: Roderick L. surname: Beijersbergen fullname: Beijersbergen, Roderick L. organization: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 8 givenname: Michel M. surname: van den Heuvel fullname: van den Heuvel, Michel M. organization: Division of Medical Oncology, Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands – sequence: 9 givenname: René surname: Bernards fullname: Bernards, René email: r.bernards@nki.nl organization: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands – sequence: 10 givenname: Michiel S. surname: van der Heijden fullname: van der Heijden, Michiel S. email: ms.vd.heijden@nki.nl organization: Division of Molecular Carcinogenesis, Cancer Genomics Netherlands, The Netherlands Cancer Institute, Amsterdam, The Netherlands |
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| Keywords | Synergy PI3K FGFR Bladder cancer |
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| SubjectTerms | Aminopyridines - pharmacology Animals Antineoplastic Combined Chemotherapy Protocols - pharmacology Benzamides - pharmacology Bladder cancer Carcinoma - drug therapy Carcinoma - enzymology Carcinoma - genetics Carcinoma - pathology Cell Line, Tumor Class I Phosphatidylinositol 3-Kinases - antagonists & inhibitors Class I Phosphatidylinositol 3-Kinases - genetics Class I Phosphatidylinositol 3-Kinases - metabolism Dose-Response Relationship, Drug Drug Resistance, Neoplasm - genetics Drug Synergism FGFR Humans Mice, Nude Molecular Targeted Therapy Morpholines - pharmacology Mutation PI3K Piperazines - pharmacology Protein Kinase Inhibitors - pharmacology Pyrazoles - pharmacology Receptors, Fibroblast Growth Factor - antagonists & inhibitors Receptors, Fibroblast Growth Factor - genetics Receptors, Fibroblast Growth Factor - metabolism RNA Interference Signal Transduction - drug effects Synergy Time Factors Transfection Tumor Burden - drug effects Urinary Bladder Neoplasms - drug therapy Urinary Bladder Neoplasms - enzymology Urinary Bladder Neoplasms - genetics Urinary Bladder Neoplasms - pathology Urology Urothelium - drug effects Urothelium - enzymology Urothelium - pathology Xenograft Model Antitumor Assays |
| Title | A Functional Genetic Screen Identifies the Phosphoinositide 3-kinase Pathway as a Determinant of Resistance to Fibroblast Growth Factor Receptor Inhibitors in FGFR Mutant Urothelial Cell Carcinoma |
| URI | https://www.clinicalkey.com/#!/content/1-s2.0-S0302283817300374 https://www.clinicalkey.es/playcontent/1-s2.0-S0302283817300374 https://dx.doi.org/10.1016/j.eururo.2017.01.021 https://www.ncbi.nlm.nih.gov/pubmed/28108151 https://www.proquest.com/docview/1861587528 |
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