Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells
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Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells. / Haltia, Ulla-Maija; Andersson, Noora; Yadav, Bhagwan; Färkkilä, Anniina; Kulesskiy, Evgeny; Kankainen, Matti; Tang, Jing; Bützow, Ralf; Riska, Annika; Leminen, Arto; Heikinheimo, Markku; Kallioniemi, Olli; Unkila-Kallio, Leila; Wennerberg, Krister; Aittokallio, Tero; Anttonen, Mikko.
I: Gynecologic Oncology, Bind 144, Nr. 3, 03.2017, s. 621-630.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells
AU - Haltia, Ulla-Maija
AU - Andersson, Noora
AU - Yadav, Bhagwan
AU - Färkkilä, Anniina
AU - Kulesskiy, Evgeny
AU - Kankainen, Matti
AU - Tang, Jing
AU - Bützow, Ralf
AU - Riska, Annika
AU - Leminen, Arto
AU - Heikinheimo, Markku
AU - Kallioniemi, Olli
AU - Unkila-Kallio, Leila
AU - Wennerberg, Krister
AU - Aittokallio, Tero
AU - Anttonen, Mikko
N1 - Copyright © 2016 Elsevier Inc. All rights reserved.
PY - 2017/3
Y1 - 2017/3
N2 - OBJECTIVE: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs.METHODS: The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells.RESULTS: Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression.CONCLUSIONS: We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options.
AB - OBJECTIVE: Resistance to standard chemotherapy poses a major clinical problem in the treatment of ovarian cancer patients. Adult-type granulosa cell tumor (AGCT) is a unique ovarian cancer subtype for which efficient treatment options are lacking in advanced disease. To this end, systematic drug response and transcriptomics profiling were performed to uncover new therapy options for AGCTs.METHODS: The responses of three primary and four recurrent AGCTs to 230 anticancer compounds were screened in vitro using a systematic drug sensitivity and resistance testing (DSRT) platform, coupled with mRNA sequencing. The responses of the AGCTs were compared with those of human granulosa luteal cells and bone marrow mononuclear cells.RESULTS: Patient-derived AGCT cells showed selective sensitivity to the Src family tyrosine kinase inhibitor dasatinib. A combination of either dasatinib or an mTOR-inhibitor everolimus with paclitaxel resulted in synergistic inhibition of AGCT cell viability. The key kinase targets of dasatinib and members of the mTOR pathway were constantly expressed at mRNA and protein levels, indicating multikinase signal addictions in the AGCT cells. Transcriptomic characterization of the tumors revealed no known oncogenic mutations, suggesting that the drug sensitivity of AGCTs was rather conveyed by selective target expression.CONCLUSIONS: We used a systematic functional approach to reveal novel treatment options for a unique gynecological cancer. The selective synergy found between taxanes and dasatinib or mTOR inhibitors warrants further clinical investigations of these combinations in relapsed or aggressive AGCTs and demonstrate that high-throughput drug screening and molecular profiling can provide an effective approach to uncover new therapy options.
KW - Aged
KW - Aged, 80 and over
KW - Antineoplastic Combined Chemotherapy Protocols/pharmacology
KW - Cell Line, Tumor
KW - Dasatinib/administration & dosage
KW - Drug Screening Assays, Antitumor
KW - Drug Synergism
KW - Female
KW - Granulosa Cell Tumor/drug therapy
KW - Humans
KW - Middle Aged
KW - Ovarian Neoplasms/drug therapy
KW - Paclitaxel/administration & dosage
KW - TOR Serine-Threonine Kinases/antagonists & inhibitors
U2 - 10.1016/j.ygyno.2016.12.016
DO - 10.1016/j.ygyno.2016.12.016
M3 - Journal article
C2 - 28104295
VL - 144
SP - 621
EP - 630
JO - Gynecologic Oncology
JF - Gynecologic Oncology
SN - 0090-8258
IS - 3
ER -
ID: 199423907