TY - JOUR
T1 - Lack of acquired resistance in HER2-positive breast cancer cells after long-term HER2 siRNA nanoparticle treatment
AU - Gu, Shenda
AU - Ngamcherdtrakul, Worapol
AU - Reda, Moataz
AU - Hu, Zhi
AU - Gray, Joe W.
AU - Yantasee, Wassana
N1 - Funding Information:
This work was funded by the National Cancer Institute (www.cancer.gov), grants HHSN261201300078C (W.Y., W.N., and J.W.G.) and R44CA217534 (W.N., W.Y., and J.W.G.), and by the Prospect Creek Foundation (W.Y. and J.W. G.). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. PDX Pharmaceuticals, LLC, a commercial company, provided support in the form of salaries for W.N. and W.Y., but did not have any additional role in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. The authors thank Tiera Liby for maintaining cell lines and the RPPA service provided by MD Anderson’s RPPA core facility, which is funded by NCI # CA16672. The authors are grateful to Dr. Tania Vu for her independent review of the data in this paper as required by OHSU conflict of interest guidelines. We also thank Dr. David Castro and Daniel Bejan for editing the manuscript.
Publisher Copyright:
© 2018 Gu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/6
Y1 - 2018/6
N2 - Intrinsic and acquired resistance to current HER2 targeted therapies remains a challenge in clinics. We have developed a therapeutic HER2 siRNA delivered using mesoporous silica nanoparticles modified with polymers and conjugated with HER2 targeting antibodies. Our previous studies have shown that our HER2 siRNA nanoparticles could overcome intrinsic and acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancers. In this study, we investigated the effect of long-term (7 months) treatment using our therapeutic HER2 siRNA. Even after the removal of HER2 siRNA, the long-term treated cells grew much slower (67% increase in doubling time) than cells that have not received any treatment. The treated cells did not undergo epithelial-mesenchymal transition or showed enrichment of tumor initiating cells. Unlike trastuzumab and lapatinib, which induced resistance in BT474 cells after 6 months of treatment, HER2 siRNA did not induce resistance to HER2 siRNA, trastuzumab, or lapatinib. HER2 ablation with HER2 siRNA prevented reactivation of HER2 signaling that was observed in cells resistant to lapatinib. Altogether, our results indicate that a HER2 siRNA based therapeutic provides a more durable inhibition of HER2 signaling in vitro and can potentially be more effective than the existing therapeutic monoclonal antibodies and small molecule inhibitors.
AB - Intrinsic and acquired resistance to current HER2 targeted therapies remains a challenge in clinics. We have developed a therapeutic HER2 siRNA delivered using mesoporous silica nanoparticles modified with polymers and conjugated with HER2 targeting antibodies. Our previous studies have shown that our HER2 siRNA nanoparticles could overcome intrinsic and acquired resistance to trastuzumab and lapatinib in HER2-positive breast cancers. In this study, we investigated the effect of long-term (7 months) treatment using our therapeutic HER2 siRNA. Even after the removal of HER2 siRNA, the long-term treated cells grew much slower (67% increase in doubling time) than cells that have not received any treatment. The treated cells did not undergo epithelial-mesenchymal transition or showed enrichment of tumor initiating cells. Unlike trastuzumab and lapatinib, which induced resistance in BT474 cells after 6 months of treatment, HER2 siRNA did not induce resistance to HER2 siRNA, trastuzumab, or lapatinib. HER2 ablation with HER2 siRNA prevented reactivation of HER2 signaling that was observed in cells resistant to lapatinib. Altogether, our results indicate that a HER2 siRNA based therapeutic provides a more durable inhibition of HER2 signaling in vitro and can potentially be more effective than the existing therapeutic monoclonal antibodies and small molecule inhibitors.
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U2 - 10.1371/journal.pone.0198141
DO - 10.1371/journal.pone.0198141
M3 - Article
C2 - 29879129
AN - SCOPUS:85048166793
SN - 1932-6203
VL - 13
JO - PLoS One
JF - PLoS One
IS - 6
M1 - e0198141
ER -