Nanoengineered Disruption of Heat Shock Protein 90 Targets Drug-Induced Resistance and Relieves Natural Killer Cell Suppression in Breast Cancer

Abstract

Drug-induced resistance, or tolerance, is an emerging yet poorly understood failure of anticancer therapy. The interplay between drug-tolerant cancer cells and innate immunity within the tumor, the consequence on tumor growth, and therapeutic strategies to address these challenges remain undescribed. Here, we elucidate the role of taxane-induced resistance on natural killer (NK) cell tumor immunity in triple-negative breast cancer (TNBC) and the design of spatiotemporally controlled nanomedicines, which boost therapeutic efficacy and invigorate “disabled” NK cells. Drug tolerance limited NK cell immune surveillance via drug-induced depletion of the NK-activating ligand receptor axis, NK group 2 member D, and MHC class I polypeptide-related sequence A, B. Systems biology supported by empirical evidence revealed the heat shock protein 90 (Hsp90) simultaneously controls immune surveillance and persistence of drug-treated tumor cells. On the basis of this evidence, we engineered a “chimeric” nanotherapeutic tool comprising taxanes and a cholesterol-tethered Hsp90 inhibitor, radicicol, which targets the tumor, reduces tolerance, and optimally reprimes NK cells via prolonged induction of NK-activating ligand receptors via temporal control of drug release in vitro and in vivo. A human ex vivo TNBC model confirmed the importance of NK cells in drug-induced death under pressure of clinically approved agents. These findings highlight a convergence between drug-induced resistance, the tumor immune contexture, and engineered approaches that consider the tumor and microenvironment to improve the success of combinatorial therapy. Significance: This study uncovers a molecular mechanism linking drug-induced resistance and tumor immunity and provides novel engineered solutions that target these mechanisms in the tumor and improve immunity, thus mitigating off-target effects.

Boosting Natural Killer Cell Therapies in Glioblastoma Multiforme Using Supramolecular Cationic Inhibitors of Heat Shock Protein 90

“…In contrast, cells treated with radicicol appeared to recover their proliferative status. These findings are consistent with our previous evidence for rapid and sustained accumulation of supramolecular drug vehicles into cells through active and passive transport mechanisms ( Smalley et al, 2020 ).…”

“…These data are consistent with other reports that interconnect adsorptive-mediated transcytosis or endocytosis with cationic particles ( Joshi et al, 2014 ; Vieira and Gamarra, 2016 ). Next, we used the optimal cationic properties from AN01 to synthesize a supramolecular cationic inhibitor of Hsp90 comprising radicicol tethered to cholesterol within a positively charged lipid bi-layer ( Smalley et al, 2020 ) and termed this new active pharmaceutical ingredient (API) “SCI-101” ( Figure 2D ). We confirmed SCI-101 maintains a uniform shape beyond 120 days, as determined by dynamic light scattering (DLS) ( Figure 2E ).…”

“…We previously reported that radicicol and radicicol-formulated nanoparticles optimally induce the expression of the NKG2D ligands MICA/B and MULT-1 in human and murine cancer models, respectively, compared to other pharmaceutical inhibitors of Hsp90 ( Smalley et al, 2020 ). This has the effect of reversing immunosuppression and improving activity of endogenous and aNK cells ( Smalley et al, 2020 ). We wanted to test the same hypothesis using drug naïve GBM models.…”

“…We recently reported a novel Hsp90 inhibitor nanoparticle using supramolecular nanochemistry to build conjugated prodrugs, which limit systemic uptake and induce NKG2D ligand expression on solid tumors, in vivo (e.g., MICA/B) ( Smalley et al, 2020 ). Here, we describe a novel treatment opportunity for GBM using the synthesized cationic supramolecular inhibitor of Hsp90 (termed “SCI-101”), which is developed for optimal crossing of the BBB in organoid models, monotherapy anticancer efficacy in 2D and 3D GBM models, and sustained expression of NK cell–activating target antigens on tumor cells for more than 72 h following treatment cessation.…”

Curcuma zedoaria petroleum ether extract reverses the resistance of triple-negative breast cancer to docetaxel via pregnane X receptor

“…At present, docetaxel is the most accessible and effective chemotherapeutic drugs for the treatment of TNBC (5). However, docetaxel tolerance has limited its therapeutic effect in TNBC and resulted in treatment failure (6). Currently, there are six known mechanisms of TNBC resistance, including the pumping of chemotherapy drugs from tumor cells by ATP binding cassette (ABC) transporter, overexpressed β-tubulin III subgroup induced paclitaxel resistance, DNA repair enzyme mutations lead to decreased sensitivity of tumor cells to chemotherapeutic drugs, the gene mutation involved in normal cell apoptosis inhibited chemotherapy-induced apoptosis of tumor cells, the effects of acetaldehyde dehydrogenase 1 (ALDH1) and glutathione/glutathione-s-transferase lead to inactivation or degradation of chemotherapeutic drugs, and effect of nuclear transcription factor-kappa B (NF-κB) signaling pathway on chemotherapy (7).…”