Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer

Leung, Wing-yin; Roxanis, Ioannis; Sheldon, Helen; Buffa, Francesca M.; Li, Jiliang; Harris, Adrian L.; Kong, Anthony

doi:10.18632/oncotarget.3296

Cited by 34 publications

(35 citation statements)

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“…Nrg1 encodes neuregulin 1 or heregulin, the predominant ligand for ERBB3, and NRG1/ERBB signals are important in cellular development such as for Schwann cells and the cardiovascular system . This signaling axis is also important in multiple cancer types and activation of the signal promotes cancer cell migration or drug resistance . Although the exact functions of TRIB1 and NRG1 in clinical cases of Ewing sarcoma remain to be clarified, the present study highlighted their potential roles as therapeutic targets and/or biomarkers.…”

Section: Discussionmentioning

confidence: 73%

“…Trib1 was identified as a leukemia disease gene that enhances MAPK phosphorylation and degrades C/EBPα . Nrg1 promotes tumor progression in many cancers such as gastric, lung, and breast cancers . Notably, these genes have been previously identified as EWS‐FLI1‐binding genes in human Ewing sarcoma .…”

Section: Resultsmentioning

confidence: 99%

“…[22][23][24] Nrg1 promotes tumor progression in many cancers such as gastric, lung, and breast cancers. [25][26][27] Notably, these genes have been previously identified as EWS-FLI1-binding genes in human Ewing sarcoma. 4 EWS-FLI1-binding peaks and an H3K27Ac active enhancer mark could be observed 30 kbp upstream from the TSS of Trib1 and 164 kbp downstream from that of Nrg1 ( Figure 3A).…”

Section: Ews-fli1 and Foxq1 Co-regulate The Transcriptional Machinerymentioning

confidence: 99%

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EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

et al. 2018

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EWS‐FLI1 constitutes an oncogenic transcription factor that plays key roles in Ewing sarcoma development and maintenance. We have recently succeeded in generating an ex vivo mouse model for Ewing sarcoma by introducing EWS‐FLI1 into embryonic osteochondrogenic progenitors. The model well recapitulates the biological characteristics, small round cell morphology, and gene expression profiles of human Ewing sarcoma. Here, we clarified the global DNA binding properties of EWS‐FLI1 in mouse Ewing sarcoma. GGAA microsatellites were found to serve as binding sites of EWS‐FLI1 albeit with less frequency than that in human Ewing sarcoma; moreover, genomic distribution was not conserved between human and mouse. Nevertheless, EWS‐FLI1 binding sites within GGAA microsatellites were frequently associated with the histone H3K27Ac enhancer mark, suggesting that EWS‐FLI1 could affect global gene expression by binding its target sites. In particular, the Fox transcription factor binding motif was frequently observed within EWS‐FLI1 peaks and Foxq1 was identified as the cooperative partner that interacts with the EWS portion of EWS‐FLI1. Trib1 and Nrg1 were demonstrated as target genes that are co‐regulated by EWS‐FLI1 and Foxq1, and are important for cell proliferation and survival of Ewing sarcoma. Collectively, our findings present novel aspects of EWS‐FLI1 function as well as the importance of GGAA microsatellites.

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Section: Discussionmentioning

confidence: 73%

Section: Resultsmentioning

confidence: 99%

Section: Ews-fli1 and Foxq1 Co-regulate The Transcriptional Machinerymentioning

confidence: 99%

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EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

et al. 2018

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“…In addition, we have previously shown that trastuzumab induced an increase of ADAM10 and ADAM17 expression, which enhanced the release of the HER ligands betacellulin and heregulin (neuregulin), resulting in activation of HER receptors as well as downstream signaling pathways during prolonged treatment with trastuzumab 42,43. A ligand-dependent mechanism has also been reported in vitro with regard to lapatinib resistance 44,45…”

Section: Introductionmentioning

confidence: 95%

“…We have recently shown that neuregulin (NRG1) can counteract the response to lapatinib, which was improved by the combination of lapatinib with pertuzumab, an antibody binding to the HER2 dimerization domain 45. It would thus be interesting to test whether NRG1 mediates resistance to neratinib and whether pertuzumab could also enhance the response to neratinib.…”

Section: Introductionmentioning

confidence: 99%

Profile of neratinib and its potential in the treatment of breast cancer

Feldinger

Kong²

2015

BCTT

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The HER (ErbB) receptor tyrosine kinase receptors are implicated in many cancers and several anti-HER treatments are now approved. In recent years, a new group of compounds that bind irreversibly to the adenosine triphosphate binding pocket of HER receptors have been developed. One of these compounds, neratinib, has passed preclinical phases and is currently undergoing various clinical trials. This manuscript reviews the preclinical as well as clinical data on neratinib. As a pan-HER inhibitor, this irreversible tyrosine kinase inhibitor binds and inhibits the tyrosine kinase activity of epidermal growth factor receptors, EGFR (or HER1), HER2 and HER4, which leads to reduced phosphorylation and activation of downstream signaling pathways. Neratinib has been shown to be effective against HER2-overexpressing or mutant tumors in vitro and in vivo. Neratinib is currently being investigated in various clinical trials in breast cancers and other solid tumors, including those with HER2 mutation. Earlier studies have already shown promising clinical activity for neratinib. However, more translational research is required to investigate biomarkers that could help to predict response and resistance for selection of appropriate patients for treatment with neratinib, either as monotherapy or in combination with other drug(s).

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Combination of lapatinib with isothiocyanates overcomes drug resistance and inhibits migration of HER2 positive breast cancer cells

Kaczyńska

Herman-Antosiewicz

2016

Breast Cancer

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BackgroundLapatinib is a commonly used drug that interrupts signaling from the epidermal growth factor receptors, EGFR and HER2/neu. Long-term exposure to lapatinib during therapy eliminates cells that are sensitive to the drug; however, at the same time it increases probability of lapatinib-resistant cell selection. The aim of this study was to verify whether combinations of lapatinib with one of isothiocyanates (sulforaphane, erucin or sulforaphene), targeting different levels of HER2 signaling pathway, exert stronger cytotoxic effect than therapy targeting the receptor only, using heterogeneous populations consisting of lapatinib-sensitive and lapatinib-resistant breast cancer cells.MethodsLapatinib-sensitive HER2 overproducing SKBR-3 breast cancer cells and their lapatinib-resistant derivatives were combined at different proportions to simulate enrichment of cancer cell population in a drug-resistant fraction during lapatinib therapy. Effects of treatments on cell survival (MTT), apoptosis induction (PARP cleavage), prosurvival signaling (p-Akt, p-S6) as well as cell motility (wound healing assay) and invasion (Boyden chamber assay) were investigated.ResultsCombination of lapatinib with any of isothiocyanates significantly decreased cell viability and inhibited migration of populations consisting of different amounts of drug-sensitive and drug-resistant cells. In case of population entirely composed of lapatinib-resistant cells the most effective was combination of lapatinib with erucin which decreased cell viability and motility, phosphorylation of Akt, S6 and VEGF level more efficiently than each agent alone.ConclusionsCombination of lapatinib and isothiocyanates, especially erucin, might be considered as an effective treatment reducing metastatic potential of breast cancer cells, even these with the drug resistance phenotype.

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Combining lapatinib and pertuzumab to overcome lapatinib resistance due to NRG1-mediated signalling in HER2-amplified breast cancer

Cited by 34 publications

References 50 publications

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

EWS‐FLI1 regulates a transcriptional program in cooperation with Foxq1 in mouse Ewing sarcoma

Profile of neratinib and its potential in the treatment of breast cancer

Combination of lapatinib with isothiocyanates overcomes drug resistance and inhibits migration of HER2 positive breast cancer cells

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