Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches
Genetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignan...
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doaj-9de8db15dce1431ab7990daeb255a41d2021-06-01T00:35:17ZengMDPI AGCancers2072-66942021-05-01132497249710.3390/cancers13102497Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising ApproachesAnna Richter0Nina Schoenwaelder1Sina Sender2Christian Junghanss3Claudia Maletzki4Department of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyDepartment of Medicine, Clinic III—Hematology, Oncology, Palliative Medicine, Rostock University Medical Center, 18057 Rostock, GermanyGenetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignancies. Incorporation of CDK inhibitors (CDKIs) into the existing therapeutic regimens therefore constitutes a promising strategy. However, the complex molecular heterogeneity and different clinical presentation is challenging for selecting the right target and defining the ideal combination to mediate long-term disease control. Preclinical and early clinical data suggest that specific CDKIs have activity in selected patients, dependent on the existing rearrangements and mutations, potentially acting as biomarkers. Indeed, CDK6, expressed in hematopoietic cells, is a direct target of MLL fusion proteins often observed in acute leukemia and thus contributes to leukemogenesis. The high frequency of aberrancies in the retinoblastoma pathway additionally warrants application of CDKIs in hematopoietic neoplasms. In this review, we describe the preclinical and clinical advances recently made in the use of CDKIs. These include the FDA-approved CDK4/6 inhibitors, traditional and novel pan-CDKIs, as well as dual kinase inhibitors. We additionally provide an overview on molecular mechanisms of response vs. resistance and discuss open questions.https://www.mdpi.com/2072-6694/13/10/2497CDK4/6 inhibitorspredictive biomarkermechanisms of resistancepharmacological inhibitioncombination strategies |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Anna Richter Nina Schoenwaelder Sina Sender Christian Junghanss Claudia Maletzki |
spellingShingle |
Anna Richter Nina Schoenwaelder Sina Sender Christian Junghanss Claudia Maletzki Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches Cancers CDK4/6 inhibitors predictive biomarker mechanisms of resistance pharmacological inhibition combination strategies |
author_facet |
Anna Richter Nina Schoenwaelder Sina Sender Christian Junghanss Claudia Maletzki |
author_sort |
Anna Richter |
title |
Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches |
title_short |
Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches |
title_full |
Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches |
title_fullStr |
Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches |
title_full_unstemmed |
Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches |
title_sort |
cyclin-dependent kinase inhibitors in hematological malignancies—current understanding, (pre-)clinical application and promising approaches |
publisher |
MDPI AG |
series |
Cancers |
issn |
2072-6694 |
publishDate |
2021-05-01 |
description |
Genetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignancies. Incorporation of CDK inhibitors (CDKIs) into the existing therapeutic regimens therefore constitutes a promising strategy. However, the complex molecular heterogeneity and different clinical presentation is challenging for selecting the right target and defining the ideal combination to mediate long-term disease control. Preclinical and early clinical data suggest that specific CDKIs have activity in selected patients, dependent on the existing rearrangements and mutations, potentially acting as biomarkers. Indeed, CDK6, expressed in hematopoietic cells, is a direct target of MLL fusion proteins often observed in acute leukemia and thus contributes to leukemogenesis. The high frequency of aberrancies in the retinoblastoma pathway additionally warrants application of CDKIs in hematopoietic neoplasms. In this review, we describe the preclinical and clinical advances recently made in the use of CDKIs. These include the FDA-approved CDK4/6 inhibitors, traditional and novel pan-CDKIs, as well as dual kinase inhibitors. We additionally provide an overview on molecular mechanisms of response vs. resistance and discuss open questions. |
topic |
CDK4/6 inhibitors predictive biomarker mechanisms of resistance pharmacological inhibition combination strategies |
url |
https://www.mdpi.com/2072-6694/13/10/2497 |
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