Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer
Abstract 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...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2017-08-01
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| Series: | Breast Cancer Research |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s13058-017-0878-6 |
| _version_ | 1818410865713479680 |
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| author | Natalia Paez Arango Erkan Yuca Ming Zhao Kurt W. Evans Stephen Scott Charissa Kim Ana Maria Gonzalez-Angulo Filip Janku Naoto T. Ueno Debu Tripathy Argun Akcakanat Aung Naing Funda Meric-Bernstam |
| author_facet | Natalia Paez Arango Erkan Yuca Ming Zhao Kurt W. Evans Stephen Scott Charissa Kim Ana Maria Gonzalez-Angulo Filip Janku Naoto T. Ueno Debu Tripathy Argun Akcakanat Aung Naing Funda Meric-Bernstam |
| author_sort | Natalia Paez Arango |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-14T10:22:19Z |
| format | Article |
| id | doaj.art-aa1049178cee4907862f726c8c7667ec |
| institution | Directory Open Access Journal |
| issn | 1465-542X |
| language | English |
| last_indexed | 2024-12-14T10:22:19Z |
| publishDate | 2017-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Breast Cancer Research |
| spelling | doaj.art-aa1049178cee4907862f726c8c7667ec2022-12-21T23:06:31ZengBMCBreast Cancer Research1465-542X2017-08-0119111010.1186/s13058-017-0878-6Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancerNatalia Paez Arango0Erkan Yuca1Ming Zhao2Kurt W. Evans3Stephen Scott4Charissa Kim5Ana Maria Gonzalez-Angulo6Filip Janku7Naoto T. Ueno8Debu Tripathy9Argun Akcakanat10Aung Naing11Funda Meric-Bernstam12Department of Surgical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Genetics, The University of Texas MD Anderson Cancer CenterDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Breast Medical Oncology, The University of Texas MD Anderson Cancer CenterDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Investigational Cancer Therapeutics, The University of Texas MD Anderson Cancer CenterDepartment of Surgical Oncology, The University of Texas MD Anderson Cancer CenterAbstract 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.http://link.springer.com/article/10.1186/s13058-017-0878-6Breast cancerSelinexorXPO1PDXTNBC |
| spellingShingle | Natalia Paez Arango Erkan Yuca Ming Zhao Kurt W. Evans Stephen Scott Charissa Kim Ana Maria Gonzalez-Angulo Filip Janku Naoto T. Ueno Debu Tripathy Argun Akcakanat Aung Naing Funda Meric-Bernstam Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer Breast Cancer Research Breast cancer Selinexor XPO1 PDX TNBC |
| title | Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer |
| title_full | Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer |
| title_fullStr | Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer |
| title_full_unstemmed | Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer |
| title_short | Selinexor (KPT-330) demonstrates anti-tumor efficacy in preclinical models of triple-negative breast cancer |
| title_sort | selinexor kpt 330 demonstrates anti tumor efficacy in preclinical models of triple negative breast cancer |
| topic | Breast cancer Selinexor XPO1 PDX TNBC |
| url | http://link.springer.com/article/10.1186/s13058-017-0878-6 |
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