Alternate actions of CDK4/6 inhibitors beyond cell cycle blockade: unexplored roles in therapy resistance

Cell cycle dysregulation and the aberrant activation of cyclin-dependent kinases (CDKs) lead to uncontrolled cell proliferation; therefore, these events represent well-established hallmarks of cancer. The advent of CDK4/6 inhibitors, namely, palbociclib, ribociclib and abemaciclib, has changed the management of oestrogen receptor (ER)-positive/HER2-negative advanced breast tumours. The clinical success of these drugs for the treatment of breast cancer has encouraged diverse clinical trials aimed at exploring novel combinatorial regimens of CDK4/6 inhibitors in different types of tumours. Hence, a comprehensive understanding of the mechanisms of action of these agents is essential to extend their benefits. Emerging evidence suggests that CDK4/6 inhibitors exert antitumour activity through other mechanisms beyond the acknowledged ability to block the cell cycle, including the induction of stress response pathways, the reprogramming of cancer cell metabolism, the modulation of the tumour microenvironment, the enhancement of the antitumour immune responses and the reduction of immune evasion. Nonetheless, the acquired resistance to CDK4/6 inhibitors remains a major therapeutic challenge. Thus, the identification of molecular drivers involved in the resistance to these drugs is crucial for the design of novel therapeutic approaches and the selection of patient-centred strategies in various types of tumours.