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

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