Klin Onkol 2018; 31(4): 305-308. DOI: 10.14735/amko2018305.
The current oncology practice recommends that all newly diagnosed breast cancers (BC) be evaluated for PR (progestogen receptor) and OR (oestrogen receptor) protein expression by immunohistochemistry [1]. Approximately 70% of patients with metastatic BC have hormone receptor positive (HR+) disease and are commonly treated with hormone-based therapies that include a non-steroidal aromatase inhibitor (NSAI) such as letrozole, anastrozole, or exemestane [2,3]. However, some patients have intrinsic resistance or acquired tolerance to hormone or endocrine therapy, which hampers their survival prolongation [4]. Thus, novel and effective therapies are urgently required for the BC population treated with endocrine therapy.
Cancer derives from uncontrolled cell division, which results from dysregulation of the cell cycle progression, including four stages, G1 (Gap phase 1), S phase (DNA synthesis), G2 (Gap phase 2), and M phase (mitosis). Cyclin D1 is a major transcriptional target of the ER. The cyclin D1-CDK4-RB pathway regulates cell proliferation by controlling the G1 to S cell cycle checkpoint [5,6]. The OR factor (E2F) family of transcription factors are downstream targets of the RB protein, which function in the cell cycle control and contribute to tumour development [7]. The combination of RB and E2F causes suppression of E2F transcription modules through inducing recruitment of the chromatin remodelling proteins, histone modifiers, and repressive chromatin marks, resulting in cell cycle block [8]. Therefore, the essential roles of CDK4/6 in the cell cycle regulation make them effective targets for cancer therapeutic intervention, especially in BC [9–11]. Fig. 1 shows details of the mechanism of action of the CDK4/6-inhibitors.
