Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL
Abstract Background Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action...
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BMC
2018-10-01
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Series: | BMC Cancer |
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Online Access: | http://link.springer.com/article/10.1186/s12885-018-4852-1 |
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record_format |
Article |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Alex J Eustace Neil T Conlon Martina S J McDermott Brigid C Browne Patrick O’Leary Frankie A Holmes Virginia Espina Lance A Liotta Joyce O’Shaughnessy Clair Gallagher Lorraine O’Driscoll Sweta Rani Stephen F Madden Neil A O’Brien Charles Ginther Dennis Slamon Naomi Walsh William M Gallagher Radoslaw Zagozdzon William R Watson Norma O’Donovan John Crown |
spellingShingle |
Alex J Eustace Neil T Conlon Martina S J McDermott Brigid C Browne Patrick O’Leary Frankie A Holmes Virginia Espina Lance A Liotta Joyce O’Shaughnessy Clair Gallagher Lorraine O’Driscoll Sweta Rani Stephen F Madden Neil A O’Brien Charles Ginther Dennis Slamon Naomi Walsh William M Gallagher Radoslaw Zagozdzon William R Watson Norma O’Donovan John Crown Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL BMC Cancer ErbB2 MCL-1 AKT FOXO3a cFLIP |
author_facet |
Alex J Eustace Neil T Conlon Martina S J McDermott Brigid C Browne Patrick O’Leary Frankie A Holmes Virginia Espina Lance A Liotta Joyce O’Shaughnessy Clair Gallagher Lorraine O’Driscoll Sweta Rani Stephen F Madden Neil A O’Brien Charles Ginther Dennis Slamon Naomi Walsh William M Gallagher Radoslaw Zagozdzon William R Watson Norma O’Donovan John Crown |
author_sort |
Alex J Eustace |
title |
Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL |
title_short |
Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL |
title_full |
Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL |
title_fullStr |
Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL |
title_full_unstemmed |
Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL |
title_sort |
development of acquired resistance to lapatinib may sensitise her2-positive breast cancer cells to apoptosis induction by obatoclax and trail |
publisher |
BMC |
series |
BMC Cancer |
issn |
1471-2407 |
publishDate |
2018-10-01 |
description |
Abstract Background Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells. Methods We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer. Results In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells. Conclusions Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies. |
topic |
ErbB2 MCL-1 AKT FOXO3a cFLIP |
url |
http://link.springer.com/article/10.1186/s12885-018-4852-1 |
work_keys_str_mv |
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doaj-5de7181f330d45b98eeaa2bf7e64c8192020-11-25T02:06:54ZengBMCBMC Cancer1471-24072018-10-0118111410.1186/s12885-018-4852-1Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAILAlex J Eustace0Neil T Conlon1Martina S J McDermott2Brigid C Browne3Patrick O’Leary4Frankie A Holmes5Virginia Espina6Lance A Liotta7Joyce O’Shaughnessy8Clair Gallagher9Lorraine O’Driscoll10Sweta Rani11Stephen F Madden12Neil A O’Brien13Charles Ginther14Dennis Slamon15Naomi Walsh16William M Gallagher17Radoslaw Zagozdzon18William R Watson19Norma O’Donovan20John Crown21Molecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversityMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversityMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversityMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversityUCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College DublinTexas Oncology-Memorial Hermann Memorial City, US Oncology ResearchGeorge Mason UniversityGeorge Mason UniversityBaylor-Sammons Cancer Center, Texas Oncology, US OncologyMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversitySchool of Pharmacy & Pharmaceutical Sciences, and Trinity Biomedical Sciences Institute, Trinity College DublinSchool of Pharmacy & Pharmaceutical Sciences, and Trinity Biomedical Sciences Institute, Trinity College DublinMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversityDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los AngelesDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los AngelesDivision of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los AngelesMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversityUCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College DublinDepartment of Clinical Immunology, Transplantation Institute, Medical University of WarsawUCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College DublinMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversityMolecular Therapeutics for Cancer Ireland, National Institute for Cellular Biotechnology, Dublin City UniversityAbstract Background Lapatinib has clinical efficacy in the treatment of trastuzumab-refractory HER2-positive breast cancer. However, a significant proportion of patients develop progressive disease due to acquired resistance to the drug. Induction of apoptotic cell death is a key mechanism of action of lapatinib in HER2-positive breast cancer cells. Methods We examined alterations in regulation of the intrinsic and extrinsic apoptosis pathways in cell line models of acquired lapatinib resistance both in vitro and in patient samples from the NCT01485926 clinical trial, and investigated potential strategies to exploit alterations in apoptosis signalling to overcome lapatinib resistance in HER2-positive breast cancer. Results In this study, we examined two cell lines models of acquired lapatinib resistance (SKBR3-L and HCC1954-L) and showed that lapatinib does not induce apoptosis in these cells. We identified alterations in members of the BCL-2 family of proteins, in particular MCL-1 and BAX, which may play a role in resistance to lapatinib. We tested the therapeutic inhibitor obatoclax, which targets MCL-1. Both SKBR3-L and HCC1954-L cells showed greater sensitivity to obatoclax-induced apoptosis than parental cells. Interestingly, we also found that the development of acquired resistance to lapatinib resulted in acquired sensitivity to TRAIL in SKBR3-L cells. Sensitivity to TRAIL in the SKBR3-L cells was associated with reduced phosphorylation of AKT, increased expression of FOXO3a and decreased expression of c-FLIP. In SKBR3-L cells, TRAIL treatment caused activation of caspase 8, caspase 9 and caspase 3/7. In a second resistant model, HCC1954-L cells, p-AKT levels were not decreased and these cells did not show enhanced sensitivity to TRAIL. Furthermore, combining obatoclax with TRAIL improved response in SKBR3-L cells but not in HCC1954-L cells. Conclusions Our findings highlight the possibility of targeting altered apoptotic signalling to overcome acquired lapatinib resistance, and identify potential novel treatment strategies, with potential biomarkers, for HER2-positive breast cancer that is resistant to HER2 targeted therapies.http://link.springer.com/article/10.1186/s12885-018-4852-1ErbB2MCL-1AKTFOXO3acFLIP |