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

Abstract

BackgroundLapatinib 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.MethodsWe 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.ResultsIn 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.ConclusionsOur 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-4852-1) contains supplementary material, which is available to authorized users.

Interplay Between Autophagy and Wnt/β-Catenin Signaling in Cancer: Therapeutic Potential Through Drug Repositioning

“…Lapatinib is an EGFR/HER2 tyrosine kinase inhibitor, administered orally for breast cancer and other solid tumors; it was approved by the FDA in 2007 (74). Lapatinib induced autophagy in cutaneous squamous cell carcinoma via mTOR inhibition and, at the same time, decreased Wnt/β-catenin expression, leading to EMT blockade.…”

Targeted lapatinib anti-HER2/ErbB2 therapy resistance in breast cancer: opportunities to overcome a difficult problem

“…Lapatinib is a selective, reversible, ATP-competitive tyrosine kinase inhibitor that binds to both HER2 and the epidermal growth factor (EGFR/HER1) [21,27,29,[41][42][43][44][45][46][47][48][49][50][51] . Lapatinib is often combined with other agents, including chemotherapy (capecitabine, gemcitabine, or vinorelbine), anti-HER2 targeting agents (trastuzumab), and endocrine therapy (e.g., letrozole) for high risk metastatic HER2-positive patients who demonstrate clinical progression (resistance) to trastuzumab [48] .…”

“…Newer agents that include neratinib, tucatinib, margetuximab, and antibody-drug conjugate trastuzumab deruxtecan (DS-8201) are currently being evaluated in clinical trials to decipher whether these agents can benefit HER2+ breast cancer patients who are resistant to trastuzumab or lapatinib-resistance. A frequent mechanism of lapatinib resistance is through inhibition of apoptotic response pathways and pro-growth signaling, through hyperactivation or overexpression of genes including X inhibitor of apoptosis protein (XIAP) [63] , myeloid leukemia 1 [64] , and the tumor necrosis factor-related apoptosisinducing ligand [45,50,63,64] . Overexpression with activation of other tyrosine receptor kinases [such as Axl, MET, insulin-like growth factor receptor 1 (IGF-1R), and vascular endothelial growth factor (VEGF)] is another common mechanism of resistance.…”

Coptisine from Coptis chinensis exerts diverse beneficial properties: A concise review

“…It also down‐regulated PI3K and Akt expression as well as altered the downstream EMT markers such as E‐cadherin, N‐cadherin, vimentin and Snail . Apoptosis plays a vital role in the progression of multiple cancers and basically activated by a mitochondria‐induced intrinsic or a death receptor‐induced extrinsic pathway, both of which are correlated with mitochondria and Bcl‐2 family anti‐apoptotic proteins . Another two studies on HCT‐116 cells investigated the underlying mechanism of coptisine's anti‐apoptotic effect characterized by affecting diverse apoptosis‐associated targets including ROS, Bcl‐2/‐XL, Bid, Bax, cytochrome c, Apaf‐a, AIF, XIAP, caspase‐3 and caspase‐9.…”

“…25 Apoptosis plays a vital role in the progression of multiple cancers and basically activated by a mitochondria-induced intrinsic or a death receptorinduced extrinsic pathway, both of which are correlated with mitochondria and Bcl-2 family anti-apoptotic proteins. [26][27][28] Another two studies on HCT-116 cells investigated the underlying mechanism of F I G U R E 2 Non-liner relationships between CC alkaloid dosages and plasma concentration (Cmax). There is an obvious process of limitation, and the bioavailability decreased along with the elevated dosage coptisine's anti-apoptotic effect characterized by affecting diverse apoptosis-associated targets including ROS, Bcl-2/-XL, Bid, Bax, cytochrome c, Apaf-a, AIF, XIAP, caspase-3 and caspase-9.…”