Akt inhibition improves the efficacy of cabazitaxel nanomedicine in preclinical taxane-resistant cancer models.

Drug resistance remains a major challenge in achieving cures in cancer patients. Cabazitaxel has shown the ability to overcome drug resistance induced by paclitaxel and docetaxel; however, substantially high toxicity has been observed in patients receiving this agent, which compromises its efficacy. We have previously demonstrated that a polymeric platform (termed cabazitaxel-NPs) encapsulating the oligolactide-cabazitaxel conjugate exhibits desired antitumor efficacy and improved in vivo tolerability. However, we found that upon cabazitaxel treatment, cancer cells adapted to activate Akt signaling, which potentially discounts the drug efficacy. We therefore hypothesized that combing cabazitaxel nanotherapeutics with a pan-Akt inhibitor MK-2206 would synergistically sensitize the resistant cancer. In this study, we confirmed that nanoparticle formulation reduced the systemic toxicity, with higher tolerance than solution-based free cabazitaxel agent in animals. Interestingly, the activation of Akt signaling in the resistant cancer was reversed by the addition of MK-2206. In particular, the collaboration of these two ingredients was demonstrated to maximize the efficacy in vitro and in a xenograft model bearing paclitaxel-resistant tumors. Mechanistically, Akt inhibition increased the microtubule-stabilizing effect of cabazitaxel nanomedicine. Collectively, this report introduced a binary platform composed of cytotoxic nanotherapeutics and inhibitors with certain targets to combat multidrug resistance, and such a combined regimen has the potential for the clinical treatment of patients with resistant cancer.