Therapeutic siRNA for drug-resistant HER2-positive breast cancer

Abstract

HER2 is overexpressed in about 20% of breast cancers and contributes to poor prognosis. Unfortunately, a large fraction of patients have primary or acquired resistance to the HER2-targeted therapy trastuzumab, thus a multi-drug combination is utilized in the clinic, putting significant burden on patients. We systematically identified an optimal HER2 siRNA from 76 potential sequences and demonstrated its utility in overcoming intrinsic and acquired resistance to trastuzumab and lapatinib in 18 HER2-positive cancer cell lines. We provided evidence that the drug-resistant cancer maintains dependence on HER2 for survival. Importantly, cell lines did not readily develop resistance following extended treatment with HER2 siRNA. Using our recently developed nanoparticle platform, systemic delivery of HER2 siRNA to trastuzumab-resistant tumors resulted in significant growth inhibition. Moreover, the optimal HER2 siRNA could also silence an exon 16 skipped HER2 splice variant reported to be highly oncogenic and linked to trastuzumab resistance.

GRB7 dependent proliferation of basal‐like, HER‐2 positive human breast cancer cell lines is mediated in part by HER‐1 signaling

“…HCC1954 is moderately resistant (GI50 at 0.39 μM) and JIMT1 and 21MT1 are highly resistant (GI50 at greater than 2 μM) to lapatinib treatment. As a comparison, BT474 is sensitive to both lapatinib and trastuzumab treatment with GI50 at 0.05 μM and 0.12 μg per milliliter, respectively …”

Silencing the roadblocks to effective triple-negative breast cancer treatments by siRNA nanoparticles

“…Whether or not pembrolizumab resistance actually involves these hypothetical resistance mechanisms is unclear. Interestingly, nanoparticle delivery of anti- HER2 siRNA has been demonstrated to circumvent resistance mechanisms associated with trastuzumab, a humanized monoclonal antibody used for treating HER2 breast cancers (Gu et al 2016). It is tempting to speculate that silencing PD-1 or PD-L1 expression by siRNA nanoparticles may circumvent pembrolizumab resistance (Table 4), however further testing, including initial studies to determine if siRNA nanoparticles can be adapted to specifically target PD-1 expression on lymphocytes are required.…”

“…PEGylated nanoparticles are coated with a number of targeting ligands whose receptors are highly expressed on tumor cells to promote receptor-mediated endocytosis. Commonly utilized targeting ligands are summarized in Table 1 (Arosio and Casagrande 2016; Bakrania, et al 2016; Cao, et al 2011; Deng, et al 2013; Feng, et al 2014; Gu, et al 2016; Nahta and Esteva 2006; Necela, et al 2015; Parvani, et al 2015; Seitz, et al 2013; Xu, et al 2016). Importantly, these strategies significantly improve nanoparticle uptake by tumor cells.…”

Current development of targeted oligonucleotide-based cancer therapies: Perspective on HER2-positive breast cancer treatment

“…Knocking down HER2 at the mRNA level is potentially a more effective approach than merely blocking HER2 activities by conventional monoclonal antibodies or small molecule inhibitors because it circumvents resistance mediated by incomplete receptor blockage, alternative splicing and post-translational modification, mutations, and sustained phosphorylation mediated by other proteins. 91 Further, while monoclonal antibodies and small molecule inhibitors can target only certain accessible proteins (so-called “druggable targets”), RNAi can be designed to modulate virtually any gene with known mRNA sequences.…”

“…Owing to small and uniform particle size of MSNP, steric effect of PEG, and charge neutralization with siRNA, we have reported outstanding blood compatibility, low immune response, 36 and low cytotoxicity of our material. 36, 91 Nevertheless, extensive efficacy and toxicity profile of this drug candidate in mice and primates needs to be established prior to clinical evaluation.…”