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Epidermal growth factor receptor family inhibition identifies P38 Mitogen-activated protein kinase as a potential therapeutic target in bladder cancer

Epidermal growth factor receptor family inhibition identifies P38 Mitogen-activated protein kinase as a potential therapeutic target in bladder cancer
Epidermal growth factor receptor family inhibition identifies P38 Mitogen-activated protein kinase as a potential therapeutic target in bladder cancer

Objective: To investigate perturbations in downstream signalling pathway activation and potential resistance mechanisms to EGFR and/or HER2 inhibition in cell line models of bladder cancer.

Methods: We undertook a structured screening approach by phosphokinase array, followed by validation steps, to detect activated downstream signalling pathway nodes after therapeutic inhibition of EGFR and/or HER2 in bladder cancer cell lines.

Results: Erlotinib treatment of RT112 cells induced phosphorylation of 9 activated phospho-protein targets (p38 MAPK (Thr180/Tyr182), GSK-3α/β (Ser21/9), MEK1/2 (Ser218/222, Ser222/226), Akt (Ser473), TOR (Ser2448), Src (Tyr419), p27 (Thr198), p27 (Thr157) and PLCγ-1 (Tyr783)) whereas STAT4 (Tyr693) phosphorylation was reduced. Of these, p38 MAPK phosphorylation was confirmed to occur in response to inhibition of either EGFR and/or HER2 signalling through multiple validation steps including differing bladder cancer cell lines (RT112, UM-UC-3 and T24) and methods of receptor pathway inhibition (erlotinib, lapatinib, siRNA depletion of EGFR or HER2). Chemical inhibition of p38 MAPK with SB203580 led to inhibition of proliferation in RT112, UM-UC-3 and T24 cell lines (IC50 20.85 µM, 76.78 µM and 79.12 µM respectively). Fractional effect analyses indicated a synergistic interaction for inhibition of cell proliferation when combining SB203580 with lapatinib.

Conclusion: p38 MAPK is a potential therapeutic target in bladder cancer and this strategy warrants further development in this disease. It may also allow for combination therapy strategies to be developed in conjunction with EGFR and/or HER2 inhibition.

Journal Article
0090-4295
225.e1-225.e7
Mora Vidal, Regina
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Regufe da Mota, Sergio
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Hayden, Annette
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Markham, Hannah
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Douglas, James
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Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Crabb, Simon J.
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Mora Vidal, Regina
0938f547-c2fb-4603-921c-3d3b5d122499
Regufe da Mota, Sergio
fe39404b-e413-4834-97c6-0f2204b500a9
Hayden, Annette
3a43aee1-3ff0-4182-956d-b6c7b3a7f8be
Markham, Hannah
ec17dffc-bef4-4397-9c5f-dc4445c1ea98
Douglas, James
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Packham, Graham
fdabe56f-2c58-469c-aadf-38878f233394
Crabb, Simon J.
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Mora Vidal, Regina, Regufe da Mota, Sergio, Hayden, Annette, Markham, Hannah, Douglas, James, Packham, Graham and Crabb, Simon J. (2018) Epidermal growth factor receptor family inhibition identifies P38 Mitogen-activated protein kinase as a potential therapeutic target in bladder cancer. Urology, 112, 225.e1-225.e7. (doi:10.1016/j.urology.2017.10.041).

Record type: Article

Abstract

Objective: To investigate perturbations in downstream signalling pathway activation and potential resistance mechanisms to EGFR and/or HER2 inhibition in cell line models of bladder cancer.

Methods: We undertook a structured screening approach by phosphokinase array, followed by validation steps, to detect activated downstream signalling pathway nodes after therapeutic inhibition of EGFR and/or HER2 in bladder cancer cell lines.

Results: Erlotinib treatment of RT112 cells induced phosphorylation of 9 activated phospho-protein targets (p38 MAPK (Thr180/Tyr182), GSK-3α/β (Ser21/9), MEK1/2 (Ser218/222, Ser222/226), Akt (Ser473), TOR (Ser2448), Src (Tyr419), p27 (Thr198), p27 (Thr157) and PLCγ-1 (Tyr783)) whereas STAT4 (Tyr693) phosphorylation was reduced. Of these, p38 MAPK phosphorylation was confirmed to occur in response to inhibition of either EGFR and/or HER2 signalling through multiple validation steps including differing bladder cancer cell lines (RT112, UM-UC-3 and T24) and methods of receptor pathway inhibition (erlotinib, lapatinib, siRNA depletion of EGFR or HER2). Chemical inhibition of p38 MAPK with SB203580 led to inhibition of proliferation in RT112, UM-UC-3 and T24 cell lines (IC50 20.85 µM, 76.78 µM and 79.12 µM respectively). Fractional effect analyses indicated a synergistic interaction for inhibition of cell proliferation when combining SB203580 with lapatinib.

Conclusion: p38 MAPK is a potential therapeutic target in bladder cancer and this strategy warrants further development in this disease. It may also allow for combination therapy strategies to be developed in conjunction with EGFR and/or HER2 inhibition.

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1-s2.0-S0090429517311846-main - Accepted Manuscript
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More information

Accepted/In Press date: 28 October 2017
e-pub ahead of print date: 15 November 2017
Published date: February 2018
Keywords: Journal Article

Identifiers

Local EPrints ID: 416305
URI: http://eprints.soton.ac.uk/id/eprint/416305
ISSN: 0090-4295
PURE UUID: c36ab4c8-e3ca-422e-8c48-bc92698aa66f
ORCID for Sergio Regufe da Mota: ORCID iD orcid.org/0000-0002-8127-5246
ORCID for Graham Packham: ORCID iD orcid.org/0000-0002-9232-5691
ORCID for Simon J. Crabb: ORCID iD orcid.org/0000-0003-3521-9064

Catalogue record

Date deposited: 12 Dec 2017 17:30
Last modified: 26 Nov 2021 05:08

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Contributors

Author: Regina Mora Vidal
Author: Sergio Regufe da Mota ORCID iD
Author: Annette Hayden
Author: Hannah Markham
Author: James Douglas
Author: Graham Packham ORCID iD
Author: Simon J. Crabb ORCID iD

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