TY - JOUR
T1 - Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer
AU - Arango, Natalia Paez
AU - Yuca, Erkan
AU - Zhao, Ming
AU - Evans, Kurt W.
AU - Scott, Stephen
AU - Kim, Charissa
AU - Gonzalez-Angulo, Ana Maria
AU - Janku, Filip
AU - Ueno, Naoto T.
AU - Tripathy, Debu
AU - Akcakanat, Argun
AU - Naing, Aung
AU - Meric-Bernstam, Funda
N1 - Publisher Copyright:
© 2017 The Author(s).
PY - 2017/8/15
Y1 - 2017/8/15
N2 - Background: Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple-negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo. Methods: Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Cell proliferation assays were used to measure the half-maximal inhibitory concentration (IC50) and to test the effects in combination with chemotherapy. In vivo efficacy was tested both as a single agent and in combination therapy in TNBC patient-derived xenografts (PDXs). Results: Selinexor demonstrated growth inhibition in all 14 TNBC cell lines tested; TNBC cell lines were more sensitive to selinexor (median IC50 44 nM, range 11 to 550 nM) than were estrogen receptor (ER)-positive breast cancer cell lines (median IC50>1000 nM, range 40 to >1000 nM; P=0.017). In multiple TNBC cell lines, selinexor was synergistic with paclitaxel, carboplatin, eribulin, and doxorubicin in vitro. Selinexor as a single agent reduced tumor growth in vivo in four of five different TNBC PDX models, with a median tumor growth inhibition ratio (T/C: treatment/control) of 42% (range 31 to 73%) and demonstrated greater antitumor efficacy in combination with paclitaxel or eribulin (average T/C ratios of 27% and 12%, respectively). Conclusions: Collectively, these findings strongly suggest that selinexor is a promising therapeutic agent for TNBC as a single agent and in combination with standard chemotherapy.
AB - Background: Selinexor (KPT-330) is an oral agent that has been shown to inhibit the nuclear exporter XPO1. Given the pressing need for novel therapies for triple-negative breast cancer (TNBC), we sought to determine the antitumor effects of selinexor in vitro and in vivo. Methods: Twenty-six breast cancer cell lines of different breast cancer subtypes were treated with selinexor in vitro. Cell proliferation assays were used to measure the half-maximal inhibitory concentration (IC50) and to test the effects in combination with chemotherapy. In vivo efficacy was tested both as a single agent and in combination therapy in TNBC patient-derived xenografts (PDXs). Results: Selinexor demonstrated growth inhibition in all 14 TNBC cell lines tested; TNBC cell lines were more sensitive to selinexor (median IC50 44 nM, range 11 to 550 nM) than were estrogen receptor (ER)-positive breast cancer cell lines (median IC50>1000 nM, range 40 to >1000 nM; P=0.017). In multiple TNBC cell lines, selinexor was synergistic with paclitaxel, carboplatin, eribulin, and doxorubicin in vitro. Selinexor as a single agent reduced tumor growth in vivo in four of five different TNBC PDX models, with a median tumor growth inhibition ratio (T/C: treatment/control) of 42% (range 31 to 73%) and demonstrated greater antitumor efficacy in combination with paclitaxel or eribulin (average T/C ratios of 27% and 12%, respectively). Conclusions: Collectively, these findings strongly suggest that selinexor is a promising therapeutic agent for TNBC as a single agent and in combination with standard chemotherapy.
KW - Breast cancer
KW - PDX
KW - Selinexor
KW - TNBC
KW - XPO1
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U2 - 10.1186/s13058-017-0878-6
DO - 10.1186/s13058-017-0878-6
M3 - Article
C2 - 28810913
AN - SCOPUS:85028044467
SN - 1465-5411
VL - 19
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 93
ER -