Int J Biol Sci 2019; 15(3):522-532. doi:10.7150/ijbs.30572 This issue
1. Department of Medical Oncology, Jinling Clinical College of Nanjing Medical University, Nanjing 210002, China.
2. Department of Medical Oncology, Jinling Hospital, Medical School of Nanjing University, Nanjing 210002, China.
3. Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China.
4. Department of Oncology, JinTan People's Hospital, Jintan 213200, China.
5. Department of Oncology, The Affiliated Changzhou No.2 People's Hospital with Nanjing Medical University, Changzhou 213003, Jiangsu, China.
#These authors contributed equally to this work.
The dysregulation of cyclin D -Cyclin-dependent kinase 4/6 (CDK4/6)-Rb axis has been implicated in breast cancer progression and the selective CDK4/6 inhibitors have shown effective activity in advanced breast cancer, especially in tumors driven by the estrogen receptor (ER). However, resistance to these small molecular inhibitors has become an inevitable clinical issue after their initial use. Here, we investigated the potential mechanism of resistance by establishing a CDK4/6 inhibitor palbociclib-resistant breast cancer cell line (MCF-7pR). After prolonged exposure to palbociclib, we detected the loss of the ER signaling and an increase in androgen receptor (AR). Moreover, we demonstrated more localization of AR in the cell nucleus of MCF-7pR compared to the parental cell (MCF-7). We also reported that AR could promote the progression of the cell cycle. Blockade of AR signaling could reduce the level of the relative G1-S cyclins, abolish Rb phosphorylation and inhibit the activation of transcriptional programs in S phase. Furthermore, dual inhibition of AR and CDK4/6 could reverse the resistance of palbociclib both in vitro and in vivo. In sum, our studies provide evidence that AR activation promotes cell cycle progression and cell proliferation in CDK4/6 inhibitor resistance, and identify AR inhibition as a putative novel therapeutic strategy to treat CDK4/6 inhibitor resistance in cancer.
Keywords: drug resistance, breast cancer, palbociclib, enzalutamide, cell cycle