TY  - JOUR
A1  - Michaelis, Martin
A1  - Wass, Mark N.
A1  - Reddin, Ian
A1  - Voges, Yvonne
A1  - Rothweiler, Florian
A1  - Hehlgans, Stephanie
A1  - Cinatl, Jaroslav
A1  - Mernberger, Marco
A1  - Nist, Andrea
A1  - Stiewe, Thorsten
A1  - Rödel, Franz
A1  - Cinatl, Jindrich
T1  - YM155-adapted cancer cell lines reveal drug-induced heterogeneity and enable the identification of biomarker candidates for the acquired resistance setting
T2  - Cancers
N2  - 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.
KW  - acquired drug resistance
KW  - biomarkers
KW  - therapy monitoring
KW  - neuroblastoma
KW  - BIRC5
KW  - survivin
KW  - intrinsic drug resistance
Y1  - 2020
UR  - http://publikationen.ub.uni-frankfurt.de/frontdoor/index/index/docId/54471
UR  - https://nbn-resolving.org/urn:nbn:de:hebis:30:3-544714
N1  - This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
VL  - 12
IS  - 1080
PB  - MDPI
CY  - Basel
ER  -