Abstract
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.
Highlights
Overexpression or amplification of HER2 (ERBB2) occurs in several types of cancer including breast [1], ovarian [2, 3], gastric [4] and colorectal cancers [5, 6]
We previously reported that BT474 cells became resistant to 10 μg/ml of trastuzumab and 1 μM of lapatinib within 6 months of continuous treatment [36]
HER2 can bind many different receptors outside of the HER family and circumvent inhibition via receptor crosstalk and alternative signaling pathways. These adaptive changes can lead to the survival of a small population of cancer cells that persist throughout treatment, leading to the relapse of the disease
Summary
Overexpression or amplification of HER2 (ERBB2) occurs in several types of cancer including breast [1], ovarian [2, 3], gastric [4] and colorectal cancers [5, 6]. Approximately 20% of all cases fall into the HER2-positive subtype, which is an adverse prognosis factor [7]. Current therapeutic regimens include the use of monoclonal antibodies or small molecule inhibitors in combination with chemotherapy such as taxane. Approved in 1998, the humanized monoclonal antibody trastuzumab binds to domain IV of HER2 and blocks receptor homodimerization [8]. To complement the activity of trastuzumab, another monoclonal antibody, pertuzumab, was developed and it binds to domain II of HER2 to block.
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