Internal medicine

Bioinformatics

Biology

Cancer

Cyclin-dependent kinase

Epistemology

Philosophy

Metastatic breast cancer

Cell cycle

Palbociclib

Acquired resistance

Cyclin-dependent kinase 4

Breast cancer

Mechanism (biology)

Cancer research

Medicine

Cyclin-dependent kinase 2

Pharmacology

International Journal of Cancer

Deregulation of the cyclin D‐CDK4/6‐INK4‐RB pathway leading to uncontrolled cell proliferation, is frequently observed in breast cancer. Currently, three selective CDK4/6 inhibitors have been FDA approved: palbociclib, ribociclib and abemaciclib. Despite promising clinical outcomes, intrinsic or acquired resistance to CDK4/6 inhibitors has limited the success of these treatments; therefore, the development of various strategies to overcome this resistance is of great importance. We highlight the various mechanisms that are directly or indirectly responsible for resistance to CDK4/6 inhibitors, categorizing them into two broad groups; cell cycle‐specific mechanisms and cell cycle‐nonspecific mechanisms. Elucidation of the diverse mechanisms through which resistance to CDK4/6 inhibitors occurs, may aid in the design of novel therapeutic strategies to improve patient outcomes. This review summarizes the currently available knowledge regarding mechanisms of resistance to CDK4/6 inhibitors, and possible therapeutic strategies that may overcome this resistance as well.

Molecular mechanisms of resistance to CDK4/6 inhibitors in breast cancer: A review