Role of pre-metastatic niche in organ specificity of breast cancer metastasis. Influence on metastatic potential as a basis for CDK4/6-inhibition efficacy in early therapy of disseminated hormone-receptor-positive disease

Abstract

Influencing the pre-metastatic niche is a very perspective cancer treatment strategy in order of preventing metastases formation. It was found that bone marrow progenitor cells and tumor cells secreting biological compounds are key components in the formation of the pre-metastatic niche. Myeloid suppressor cells (MSCs) are the main type of bone marrow cells in pre-metastatic niches. At the same time, tumor-associated chronic inflammation induces the expression of proinflammatory cytokines triggering myeloid cells differentiation into myeloid suppressor cells. When circulating tumor cells enter the circulatory channel, their interaction with immune cells is observed, which additionally influences the pre-metastatic site preparation. Studies have shown that the entire spectrum of immune cells is capable of influencing the metastasis formation by circulating tumor cells. The epithelialmesenchymal transition with the tumor cell transporting form appearence was found to be related to the function of the ZEB1 protein. Its activity is regulated by numerous signaling mechanisms at the transcriptional level, including TGFβ, Wnt and Notch. This initiates epithelial-mesenchymal transition of breast cancer cells. Zhang Z.et al. proved that CDK4/6 blocking leads ZEB1 protein stability decreasing, preventing metastasis in breast cancer in vitro and in vivo. Moreover, USP51 deubiquitinase has been identified as a target of cyclin-dependent 4/6 kinases. At the molecular level, CDK4/6 phosphorylate and activates USP51, which then influences ZEB1  deubiquitination and stabilization. A  positive correlation was demonstrated between the  expression of p-RB (an indicator of CDK4/6 activity), p-USP51 and ZEB1 in breast cancer samples. Thus, the CDK4/6-USP51-ZEB1 axis may play a key role in the metastasis of breast cancer. In breast cancer cells, inhibition of CDK4/6 was shown to increase the expression of  E-cadherin  but decrease the  expression of  mesenchymal markers, reducing the  migratory ability and invasiveness of  breast cancer cell lines. This biological effect may also explain  the  clinical efficacy of  the  CDK4/6  inhibitor Abemaciclib in early-line therapy of metastatic breast cancer as well as in adjuvant combination hormone therapy for the prevention of metastatic lesions in patients at high risk of recurrence and progression in the MONARCH E study. Besides, there were no response predictors evaluated in trials investigating CDK4/6 in breast cancer treatment and it is unknown if there any differences in treatment response according to the metastatic site. The clinical cases demonstrate abemaciclib clinical efficacy in metastatic breast cancer treatment regardless of metastatic site.