Overexpressed Cyclin D1 and CDK4 proteins are responsible for the resistance to CDK4/6 inhibitor in breast cancer that can be reversed by PI3K/mTOR inhibitors

CDK4/6 inhibitors are the standard treatment in advanced HR+/HER2-breast cancer patients.Nevertheless,the resistance to CDK4/6 inhibitors is inevitable and the strategies to overcome resistance are of great interest.Here,we show that the palbociclibresistant breast cancer cells expressed significantly higher levels of Cyclin D1 and CDK4 proteins because of upregulated protein synthesis.Silencing Cyclin D1 or CDK4 led to cell cycle arrest while silencing Cyclin E1 or CDK2 restored the sensitivity to palbociclib.Furthermore,PI3K/mTOR pathway was hyper-activated in palbociclib-resistant cells,leading to more phosphorylated 4E-BP1 and higher levels of Cyclin D1 and CDK4 translation.Targeting PI3K/mTOR pathway with a specific PI3Kαinhibitor(BYL719)or an mTOR inhibitor(everolimus)reduced the protein levels of Cyclin D1 and CDK4,and restored the sensitivity to palbociclib.The tumor samples expressed significantly higher levels of Cyclin D1,CDK4,p-AKT and p-4E-BP1 after progression on palbociclib treatment.In conclusion,our findings suggest that overexpressed Cyclin D1 and CDK4 proteins lead to the resistance to CDK4/6 inhibitor and PI3K/mTOR inhibitors are able to restore the sensitivity to CDK4/6 inhibitors,which provides the biomarker and rationale for the combinational use of CDK4/6 inhibitors and PI3K/mTOR inhibitors after CDK4/6 inhibitor resistance in breast cancer.

Nanoparticles(NPs)-mediated systemic mRNA delivery to reverse trastuzumab resistance for effective breast cancer therapy

Monoclonal antibody-based therapy has achieved great success and is now one of the most crucial therapeutic modalities for cancer therapy.The first monoclonal antibody authorized for treating human epidermal growth receptor 2(HER2)-positive breast cancer is trastuzumab.However,resistance to trastuzumab therapy is frequently encountered and thus significantly restricts the therapeutic outcomes.To address this issue,tumor microenvironment(TME)pH-responsive nanoparticles(NPs)were herein developed for systemic mRNA delivery to reverse the trastuzumab resistance of breast cancer(BCa).This nanoplatform is comprised of a methoxyl-poly(ethylene glycol)-b-poly(lactic-co-glycolic acid)copolymer with a TME pH-liable linker(Meo-PEG-Dlinkm-PLGA)and an amphiphilic cationic lipid that can complex PTEN mRNA via electrostatic interaction.When the long-circulating mRNA-loaded NPs build up in the tumor after being delivered intravenously,they could be efficiently internalized by tumor cells due to the TME pH-triggered PEG detachment from the NP surface.With the intracellular mRNA release to up-regulate PTEN expression,the constantly activated PI3K/Akt signaling pathway could be blocked in the trastuzumab-resistant BCa cells,thereby resulting in the reversal of trastuzumab resistance and effectively suppress the development of BCa.