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TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response

Lookup NU author(s): Dr Chiao-En Wu, Tsin Koay, Professor Penny LovatORCiD, Emeritus Professor John LunecORCiD

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This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).

Abstract

© 2019 The Author(s). Background: Emergence of resistance to molecular targeted therapy constitutes a limitation to clinical benefits in cancer treatment. Cross-resistance commonly happens with chemotherapeutic agents but might not with targeted agents. Methods: In the current study, TP53 wild-type cell lines with druggable MAPK pathway mutations [BRAF V600E (WM35) or NRAS Q61K (SJSA-1)] were compared with their TP53 mutant sublines (WM35-R, SN40R2) derived by selection for resistance to MDM2/p53 binding antagonists. Results: The continued presence of the druggable MAPK pathway targets in the TP53 mutant (TP53 MUT ) WM35-R and SN40R2 cells was confirmed. Trametinib and vemurafenib were tested on the paired WM35/WM35-R and SJSA-1/SN40R2 cells and similar growth inhibitory effects on the paired cell lines was observed. However, apoptotic responses to trametinib and vemurafenib were greater in WM35 than WM35-R, evidenced by FACS analysis and caspase 3/7 activity, indicating that these MAPK inhibitors acted on the cells partially through p53-regulated pathways. SiRNA mediated p53 knockdown in WM35 replicated the same pattern of response to trametinib and vemurafenib as seen in WM35-R, confirming that p53 plays a role in trametinib and vemurafenib induced apoptosis. In contrast, these differences in apoptotic response between WM35 and WM35-R were not seen with the SJSA-1/SN40R2 cell line pair. This is likely due to p53 suppression by overexpressed MDM2 in SJSA-1. Conclusion: The TP53 MUT cells selected by resistance to MDM2 inhibitors nevertheless retained growth inhibitory but not apoptotic response to MAPK pathway inhibitors.

Publication metadata

Author(s): Wu C-E, Koay TS, Ho Y-H, Lovat P, Lunec J

Publication type: Article

Publication status: Published

Journal: Cancer Cell International

Year: 2019

Volume: 19

Issue: 1

Online publication date: 07/03/2019

Acceptance date: 28/02/2019

Date deposited: 28/03/2019

ISSN (electronic): 1475-2867

Publisher: BioMed Central Ltd

URL: https://doi.org/10.1186/s12935-019-0768-3

DOI: 10.1186/s12935-019-0768-3

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