Akt Inhibition Improves the Efficacy of Cabazitaxel Nanomedicine in Preclinical Taxane-Resistant Cancer Models
Background: Drug resistance continues to be a major clinical challenge in achieving cures in cancer patients. Cabazitaxel has shown the ability to surmount drug resistance through bypassing the transporter-mediated drug expulsion; however, the substantially high toxicity in patients hampered its clinical application. In addition, upregulation of certain self-defense proteins (e.g, Akt) was reportedly involved in drug resistance, which may further compromise the activity of cabazitaxel. We have
... reviously developed several prodrug-based strategies to deliver nanoparticles encapsulating cabazitaxel derivatives in tumors with enhanced efficacy and improved in vivo tolerability. Therefore, we hypothesized that combing cabazitaxel nanotherapeutics with a pan-Akt inhibitor MK-2206 would synergistically eliminate the resistant cancers with reduced systemic toxicity.Methods: Activation of Akt in resistant cancers upon cabazitaxel treatment was determined by western blotting assay. The effect of combing MK-2206 with cabazitaxel on cell viability was evaluated by CCK-8 assay. To improve the in vivo biocompatibility, the delivery of potent cabazitaxel was feasibly achieved via the integration of oligolactide-conjugated cabazitaxel into the PEG-b-PLA matrix. Both the synergism and safety of cabazitaxel nanomedicine-based combination were evaluated through a series of in vitro and in vivo experiments, including Western blotting assay, CCK-8 assay, EdU assay, flow cytometry, migration assay, transwell assay, MTD study, myelosuppression study, nude mouse xenograft, and immunostaining analyses. Results: We found that resistant cells adapted to activate Akt signaling upon cabazitaxel treatment, which potentially discounts the efficacy of cabazitaxel. The addition of MK-2206 reversed this situation and potentiated the activity of cabazitaxel nanomedicine against resistant cells. Mechanistically, suppression of the Akt pathway increased the microtubule-stabilizing effect of cabazitaxel. Their collaboration was demonstrated to maximize the efficacy in a xenograft model bearing paclitaxel-resistant tumors. In particular, the nanoformulation substantially improved drug tolerability in animals, and combined treatment with MK-2206 was proven to be safe for synergistic cancer therapy. Conclusion: The preclinical studies demonstrate the therapeutic efficacy of our binary system consisting of a better-tolerated nanotherapy and a specific pathway modulator against resistant cells, thereby highlighting the potential applications for the clinical treatment of patients with multidrug-resistant malignancies.