Dataset Information

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

ABSTRACT:

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.

SUBMITTER: Wu CE

PROVIDER: S-EPMC6407233 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Publications

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

Wu Chiao-En CE Koay Tsin Shue TS Ho Yi-Hsuan YH Lovat Penny P Lunec John J

Cancer cell international 20190307

<h4>Background</h4>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.<h4>Methods</h4>In the current study, <i>TP53</i> wild-type cell lines with druggable MAPK pathway mutations [<i>BRAF</i> <sup>V600E</sup> (WM35) or <i>NRAS</i> <sup>Q61K</sup> (SJSA-1)] were compared with their <i>TP53</i> mutant sublines (WM35-R, SN40R2) deriv ...[more]

PMID: 30899200

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