Cyclin-dependent kinase (CDK) 9 and 4/6 inhibitors in acute myeloid leukemia (AML): a promising therapeutic approach

ABSTRACT

Introduction: Despite advancements over the last 2 years, outcomes for acute myeloid leukemia (AML) are poor; however, a greater comprehension of disease mechanisms has driven the investigation of new targeted treatments. Cyclin-dependent kinases (CDKs) regulate cell cycle progression, transcription and DNA repair, and are aberrantly expressed in AML. Targeting the CDK pathway is an emerging promising therapeutic strategy in AML.

Areas covered: We describe the rationale for targeting CDK9 and CDK4/6, the ongoing preclinical and clinical trials and the potential of these inhibitors in AML. Our analysis included an extensive literature search via the Pubmed database and clinicaltrials.gov (March to August, 2019).

Expert opinion: While CDK4/6 inhibitors are early in development for AML, CDK9 inhibition with alvocidib has encouraging clinical activity in newly diagnosed and relapsed/refractory AML. Preclinical data suggests that leukemic MCL-1 dependence may predict response to alvocidib. Moreover, MCL-1 plays a key role in resistance to BCL-2 inhibition with venetoclax. Investigational strategies of concomitant BCL-2 and CDK9 inhibition represent a promising therapeutic platform for AML. Furthermore, preclinical data suggests that CDK4/6 inhibition has selective activity in patients with KMT2A-rearrangements and FLT3 mutations. Incorporation of CDK9 and 4/6 inhibitors into the existing therapeutic armamentarium may improve outcomes in AML.

KEYWORDS:

• Acute myeloid leukemia
• clinical trials
• cyclin dependent kinase
• CDK9
• MCL-1
• CDK6
• drug development

Article highlights

• Despite advances in AML, therapeutic options are limited for most patients with relapsed/refractory disease and outcomes are poor.

• Cyclin-dependent kinases (CDK’s) regulate cell cycle progression, transcription and DNA repair and inhibition of CDK’s represents a promising investigational approach in AML

• CDK9 inhibition down-regulates the transcription of genes such as c-MYC and MCL-1 that are involved in cell survival

• CDK4/6 inhibition leads to cell cycle arrest in G1 phase and is a promising therapeutic approach in KMT2A (MLL)-rearranged and FLT3-mutated AML

• Alvocidib (flavopiridol), a CDK9 inhibitor, has shown the most promise as a CDK inhibitor in AML

• Alvocidib has demonstrated clinical activity when combined with cytarabine and mitoxantrone (FLAM) in newly diagnosed and relapsed/refractory AML.

• Biomarker-based strategies to identify patients most likely to benefit from CDK inhibition in AML is a future challenge

Declaration of interest

JF Zeidner has received honoraria from AbbVie, Agios, Celgene, Daiichi Sankyo, Pfizer, and Tolero. He has also served as a Consultant for AsystBio Laboratories, and Celgene and has received research funding from Celgene, Merck, Takeda, and Tolero.

DJ Lee has served as a Consultant for Boston Biomedical, and has received research funding from Abbvie, Bayer, F. Hoffman-La Roche, Forty Seven, and Tolero. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose

Additional information

Funding

This paper was not funded.