MicroRNA in combination with HER2-targeting drugs reduces breast cancer cell viability in vitro

Date 03 May 2019
Event ESMO Breast Cancer 2019
Session Poster lunch
Topics Breast Cancer
Basic Science
Presenter Lisa Svartdal
Citation Annals of Oncology (2019) 30 (suppl_3): iii1-iii26. 10.1093/annonc/mdz095
Authors L.G. Svartdal1, M.R. Aure2, S. Leivonen3, M.H. Haugen4, V. Hongisto5, V.N. Kristensen6, G.M. Mælandsmo4, K.K. Sahlberg1
  • 1Research Unit, Vestre Viken Health Trust, 3019 - Drammen/NO
  • 2Cancer Genetics, Oslo University Hospital, 0379 - Oslo/NO
  • 3Research Programs Unit, Applied Tumor Genomics, University of Helsinki, Helsinki/FI
  • 4Division Of Cancer Medicine - Institute For Cancer Research - Dept.tumor Biology, Oslo University Hospital - The Norwegian Radium Hospital, N-0424 - Oslo/NO
  • 5Toxicology, Milvik Biology Oy, Turku/FI
  • 6Molecular Biology, Epigen, Akershus universitetssykehus HF, 1478 - Lorenskog/NO

Abstract

Background

Human epidermal growth factor receptor 2 positive (HER2+) breast cancer is an aggressive cancer form due to regulation and initiation of intracellular signaling pathways that promote cell survival and proliferation. Although HER2-targeted therapy, like trastuzumab and lapatinib, has improved outcome for HER2+ breast cancer patients, not all patients respond to treatment. We hypothesize that HER2+ breast cancer cells with poor response to targeted treatment can be sensitized by combining microRNAs (miRNAs) with traditional targeted therapy.

Methods

Two HER2+ cell lines with poor response to trastuzumab and lapatinib, KPL4 and SUM190, were transfected with a panel of 810 miRNA mimics and 816 inhibitors. The cells were treated with the miRNAs alone and in combination with trastuzumab and/or lapatinib. Viability was measured after incubation for 72 hours. In addition, cell lysates were prepared and protein expression of cPARP, KI67, AKT, pAKT, ERK, pERK, HER2, pHER2-Y1222 and pHER2-Y877 were measured using a lysate microarray. Based on the findings, 17 miRNAs were chosen for further validation.

Results

Of the 17 miRNAs validated from the screen, eight miRNAs show a sensitization effect and significantly improve the effect of trastuzumab and lapatinib in vitro. The cell viability is reduced with 14-83 % by the miRNAs alone compared to negative control; 14-76 % compared to trastuzumab; 18-69 % compared to lapatinib; and 13-59 % compared to the two drugs in combination. The protein lysate arrays show that some of the miRNAs affect the protein expression levels, and this will be further explored.

Conclusions

Eight miRNAs in combination with the HER2-targeting drugs trastuzumab and lapatinib reduce breast cancer cell viability in vitro. This implies the potential of miRNAs as a combinatorial therapeutic together with targeted drugs to improve the effect for poor-responding HER2+ breast cancer patients.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

Research Unit, Vestre Viken HF.

Funding

South-Eastern Norway Regional Health Authority.

Disclosure

All authors have declared no conflicts of interest.