YM155-Adapted Cancer Cell Lines Reveal Drug-Induced Heterogeneity and Enable the Identification of Biomarker Candidates for the Acquired Resistance Setting.

Martin Michaelis,Ian Reddin,Stephanie Hehlgans,Thorsten Stiewe,Jaroslav Cinatl,Andrea Nist,Marco Mernberger,Mark N Wass,Florian Rothweiler,Franz Rödel,Yvonne Voges,Jindrich Cinatl

doi:10.3390/cancers12051080

Abstract

Survivin is a drug target and its suppressant YM155 a drug candidate mainly investigated for high-risk neuroblastoma. Findings from one YM155-adapted subline of the neuroblastoma cell line UKF-NB-3 had suggested that increased ABCB1 (mediates YM155 efflux) levels, decreased SLC35F2 (mediates YM155 uptake) levels, decreased survivin levels, and TP53 mutations indicate YM155 resistance. Here, the investigation of 10 additional YM155-adapted UKF-NB-3 sublines only confirmed the roles of ABCB1 and SLC35F2. However, cellular ABCB1 and SLC35F2 levels did not indicate YM155 sensitivity in YM155-naïve cells, as indicated by drug response data derived from the Cancer Therapeutics Response Portal (CTRP) and the Genomics of Drug Sensitivity in Cancer (GDSC) databases. Moreover, the resistant sublines were characterized by a remarkable heterogeneity. Only seven sublines developed on-target resistance as indicated by resistance to RNAi-mediated survivin depletion. The sublines also varied in their response to other anti-cancer drugs. In conclusion, cancer cell populations of limited intrinsic heterogeneity can develop various resistance phenotypes in response to treatment. Therefore, individualized therapies will require monitoring of cancer cell evolution in response to treatment. Moreover, biomarkers can indicate resistance formation in the acquired resistance setting, even when they are not predictive in the intrinsic resistance setting.

Highlights

Sepantronium bromide (YM155) was introduced as an anti-cancer drug candidate that inhibits expression of the BIRC5 gene, which encodes the protein survivin [1]
The YM155-adapted UKF-NB-3 sublines displayed between 38- and 76-fold increased YM155
A YM155-adapted subline of the neuroblastoma cell line UKF-NB-3 was characterized by increased cellular ABCB1 levels, decreased SLC35F2 and survivin levels, and a characterized by increased cellular ABCB1 levels, decreased SLC35F2 and survivin levels, and a TP53

Summary

Introduction

Sepantronium bromide (YM155) was introduced as an anti-cancer drug candidate that inhibits expression of the BIRC5 gene, which encodes the protein survivin [1]. YM155 has been suggested to exert additional and/or alternative mechanisms of anticancer actions, including induction. Cancers 2020, 12, 1080 of DNA damage, inhibition of NFκB signaling, induction of death receptor 5 expression, and/or suppression of MCL-1, XIAP, cIAP-1/2, BCL-2, BCL-XL, FLIP, EGFR, and/or mTORC [2,3,4,5,6,7,8,9,10,11,12,13]. Treatment outcomes in high-risk neuroblastoma patients remain unsatisfactory. We have recently shown that suppression of survivin expression is the main mechanism through which YM155 exerts its anti-neuroblastoma effects [16]

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Discussion

Conclusion