Type

Journal Article

Authors

John Crown
Norma O'Donovan
William R Watson
Radoslaw Zagozdzon
William M Gallagher
Naomi Walsh
Dennis Slamon
Charles Ginther
Neil A O'Brien
Stephen F Madden
and 12 others

Subjects

Microbiology

Topics
gene expression antineoplastic agents drug therapy cflip female therapeutic use genes erbb 2 forkhead box protein o3 genetics lapatinib metabolism biosynthesis drug resistance neoplasm akt foxo3a cell line tumor cancer phosphorylation pathology pharmacology tnf related apoptosis inducing ligand apoptosis mcl 1 proto oncogene proteins c bcl 2 drug effects breast cancer fadd like apoptosis regulating protein breast neoplasms casp8 humans bcl 2 family erbb2

Development of acquired resistance to lapatinib may sensitise HER2-positive breast cancer cells to apoptosis induction by obatoclax and TRAIL. (2018)

Abstract 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. 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. 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. 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.
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Full list of authors on original publication

John Crown, Norma O'Donovan, William R Watson, Radoslaw Zagozdzon, William M Gallagher, Naomi Walsh, Dennis Slamon, Charles Ginther, Neil A O'Brien, Stephen F Madden and 12 others

Experts in our system

1
John Crown
Dublin City University
Total Publications: 104
 
2
Norma O'Donovan
Dublin City University
Total Publications: 59
 
3
William R Watson
Trinity College Dublin
 
4
Radoslaw Zagozdzon
Trinity College Dublin
Total Publications: 5
 
5
William M Gallagher
University College Dublin
Total Publications: 148
 
6
Naomi Walsh
Dublin City University
Total Publications: 22
 
7
Neil A O'Brien
Dublin City University
Total Publications: 9
 
8
Stephen F Madden
Dublin City University
Total Publications: 45