Systematic drug sensitivity testing reveals synergistic growth inhibition by dasatinib or mTOR inhibitors with paclitaxel in ovarian granulosa cell tumor cells

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 - 2017/3/1

Y1 - 2017/3/1

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

SN - 0090-8258

VL - 144

SP - 621

EP - 630

JO - Gynecologic Oncology

JF - Gynecologic Oncology

IS - 3

ER -