CDK6 Inhibition: A Novel Approach in AML Management.

Iris Z Uras,Karoline Kollmann,Veronika Sexl

doi:10.3390/ijms21072528

Abstract

Acute myeloid leukemia (AML) is a complex disease with an aggressive clinical course and high mortality rate. The standard of care for patients has only changed minimally over the past 40 years. However, potentially useful agents have moved from bench to bedside with the potential to revolutionize therapeutic strategies. As such, cell-cycle inhibitors have been discussed as alternative treatment options for AML. In this review, we focus on cyclin-dependent kinase 6 (CDK6) emerging as a key molecule with distinct functions in different subsets of AML. CDK6 exerts its effects in a kinase-dependent and -independent manner which is of clinical significance as current inhibitors only target the enzymatic activity.

Highlights

Acute myeloid leukemia (AML), which accounts for 75% of acute leukemia, is an aggressive disease with a complex and heterogeneous background characterized by rapid proliferation of hematopoietic progenitor cells frequently lacking terminal differentiation
The heterogeneity of the disease poses a huge problem for therapeutic strategies—AML comprises a group of morphologically and genetically distinct malignancies characterized by an aberrant clonal proliferation of myeloid progenitor cells
Subsequent work extended these findings in FLT3-D835Y+ cells and revealed additional transcriptional targets of cyclin-dependent kinase 6 (CDK6) that are required for the viability and expansion of FLT3-mutant cells. reAqus isruecdhf,oAruthroeravikaibnialistey(aAnUdReKxp) aannsdioAnKoTf aFrLeTi3d-emntuifitaendt acselClsD

Summary

Introduction

Acute myeloid leukemia (AML), which accounts for 75% of acute leukemia, is an aggressive disease with a complex and heterogeneous background characterized by rapid proliferation of hematopoietic progenitor cells frequently lacking terminal differentiation. The treatment modalities for AML include chemotherapy and allogeneic hematopoietic stem cell (HSC) transplantation. Despite these efforts, the outcome is poor with a five-year relative survival of only 17–19% [1,2]. Various compounds including tyrosine kinase inhibitors, immune checkpoint inhibitors, cell-cycle inhibitors, monoclonal or bispecific T-cell engager antibodies, and metabolic and proapoptotic agents are currently under investigation in clinical trials [4,5]. This novel and exciting repertoire of strategies, occasionally in combination with standard chemotherapeutics, has drastically broadened the opportunities of AML treatment.

The Specific Functions of CDK6

CDK6 Protein Degradation Versus CDK6 Kinase Inhibition

CDK6 Inhibitors in Clinical Trials for AML

Findings

Conclusions