Abstract 3034: TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response

Abstract

Emergence of resistance to molecular targeted therapy constitutes a potential limitation to clinical benefits in cancer treatment. Cross-resistance commonly happens with chemotherapeutic agents but might not with targeted agents. In the current study, TP53 wild -type cell lines with druggable MAPK pathway mutations (BRAFV600E (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. The continued presence of the druggable MAPK pathway targets in the TP53 mutant (TP53MUT) 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 knockdown of p53 expression 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. In conclusion, the TP53MUT cells selected by resistance to MDM2 inhibitors nevertheless retained growth inhibitory but not apoptotic response to MAPK pathway inhibitors. Citation Format: Chiao-En Wu, Tsin Shue Koay, Yi-Hsuan Ho, Penny Lovat, John Lunec. TP53 mutant cell lines selected for resistance to MDM2 inhibitors retain growth inhibition by MAPK pathway inhibitors but a reduced apoptotic response [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3034.

In Vitro/In Vivo Translation of Synergistic Combination of MDM2 and MEK Inhibitors in Melanoma Using PBPK/PD Modelling: Part I

“…Resistance is an inherent part of anticancer treatment; therefore, the population of resistant cells was assessed for both drugs in the performed study, the description of which may play a critical role in predicting and optimizing treatment response and may improve therapy scheduling [ 35 , 36 ]. However, further in vitro studies on drug-resistant A375 melanoma sublines with the Siremadlin and Trametinib combination would be needed for in-depth analysis of resistance mechanisms, and to test if such combination treatment would be suitable for prolonged treatment, which is often characterized by increased resistance [ 7 , 37 , 38 , 39 , 40 , 41 , 42 ]. Results from drug interaction analysis indicated synergistic interaction between the drugs studied in an A375 melanoma model.…”