Mechanisms of resistance to cyclin-dependent kinase 4/6 inhibitors

Georgia Gomatou; Ioannis Trontzas; Stephanie Ioannou; Maria Drizou; Nikolaos Syrigos; Elias Kotteas

doi:10.1007/s11033-020-06100-3

Mechanisms of resistance to cyclin-dependent kinase 4/6 inhibitors

Mol Biol Rep. 2021 Jan;48(1):915-925. doi: 10.1007/s11033-020-06100-3. Epub 2021 Jan 7.

Authors

Georgia Gomatou¹, Ioannis Trontzas², Stephanie Ioannou², Maria Drizou², Nikolaos Syrigos², Elias Kotteas²

Affiliations

¹ Oncology Unit, 3rd Department of Medicine, 'Sotiria' General Hospital, National and Kapodistrian University of Athens, Athens, Greece. [email protected].
² Oncology Unit, 3rd Department of Medicine, 'Sotiria' General Hospital, National and Kapodistrian University of Athens, Athens, Greece.

PMID: 33409716
DOI: 10.1007/s11033-020-06100-3

Abstract

Cyclin-dependent kinase (CDK) 4/6 inhibitors have emerged in the treatment of metastatic hormone receptor (HR)-positive and human epidermal growth factor receptor 2 (HER2)-negative breast cancer. However, most patients will eventually present disease progression, highlighting the inevitable resistance of cancer cells to CDK4/6 inhibition. Several studies have suggested that resistance mechanisms involve aberrations of the molecules that regulate the cell cycle, and the re-wiring of the cell to escape CDK4/6 dependence and turn to alternative pathways. Loss of retinoblastoma function, overexpression of CDK 6, upregulation of cyclin E, overexpression of CDK 7, and dysregulation of several signaling pathways, notably the PI3/AKT/mTOR pathway, have been implicated in the development of resistance to CDK4/6 inhibitors. Overlap with endocrine resistance mechanisms might be possible. Combinational therapeutic strategies should be explored in order to prevent resistance and optimize the management of patients after progression under CDK 4/6 inhibition.

Keywords: Breast Cancer; CDK 4/6 inhibitors; Cyclin-dependent kinase; Resistance.

Publication types

Review

MeSH terms

Antineoplastic Agents / therapeutic use
Breast Neoplasms / drug therapy
Breast Neoplasms / genetics*
Breast Neoplasms / metabolism
Breast Neoplasms / pathology
Cell Cycle / drug effects
Cell Cycle / genetics
Cyclin E / genetics
Cyclin E / metabolism
Cyclin-Dependent Kinase 4 / antagonists & inhibitors
Cyclin-Dependent Kinase 4 / genetics*
Cyclin-Dependent Kinase 4 / metabolism
Cyclin-Dependent Kinase 6 / antagonists & inhibitors
Cyclin-Dependent Kinase 6 / genetics*
Cyclin-Dependent Kinase 6 / metabolism
Cyclin-Dependent Kinase-Activating Kinase
Cyclin-Dependent Kinases / antagonists & inhibitors
Cyclin-Dependent Kinases / genetics
Cyclin-Dependent Kinases / metabolism
Disease Progression
Drug Resistance, Neoplasm / drug effects
Drug Resistance, Neoplasm / genetics*
Female
Gene Expression Regulation, Neoplastic*
Humans
Molecular Targeted Therapy / methods
Oncogene Proteins / genetics
Oncogene Proteins / metabolism
Protein Kinase Inhibitors / therapeutic use
Receptor, ErbB-2 / genetics
Receptor, ErbB-2 / metabolism
Retinoblastoma Protein / genetics
Retinoblastoma Protein / metabolism
Signal Transduction
TOR Serine-Threonine Kinases / genetics
TOR Serine-Threonine Kinases / metabolism

Substances

Antineoplastic Agents
CCNE1 protein, human
Cyclin E
Oncogene Proteins
Protein Kinase Inhibitors
Retinoblastoma Protein
MTOR protein, human
ERBB2 protein, human
Receptor, ErbB-2
TOR Serine-Threonine Kinases
CDK4 protein, human
CDK6 protein, human
Cyclin-Dependent Kinase 4
Cyclin-Dependent Kinase 6
Cyclin-Dependent Kinases
Cyclin-Dependent Kinase-Activating Kinase