CDK6: an attractive therapeutic target for T-ALL/LBL

ABSTRACT

Introduction

Human T-cell acute lymphoblastic leukemia/T-cell lymphoblastic lymphoma (T-ALL/LBL) is a type of cancer that originates from the bone marrow and spreads quickly to other organs. Long-term survival rate with current available chemotherapy is less than 20%. Despite the potentially huge market, a truly effective and safe therapy for T-ALL/LBL is elusive. Thus, it is imperative to identify new therapeutic ways to target essential pathways in T-ALL that regulate the proliferation and survival of these cancer cells.

Areas covered

The role of the Cyclin-dependent kinase 6 (CDK6) pathway in human T-ALL is of significant interest with major clinical/translational relevance. This review covers the recent advances in elucidating the essential roles of CDK6 and its closely regulated networks in proliferation, survival, and metabolism of T-ALL cells, with new insight into its mechanisms of action which hopefully could trigger the identification of new therapeutic avenues.

Expert opinion

Animal models showed that inhibition of CDK6 and its related networks blocked initiation, growth, and survival of T-ALL in vivo. Numerous clinical trials of CDK4/6 inhibitors are ongoing in T-ALL. Specific CDK6 inhibitors alone or novel combination regimens may hopefully delay the progression, or even reverse the symptoms of T-ALL, leading to disease eradication and cure.

KEYWORDS:

• Cyclin-dependent kinase 6 (CDK6)
• cell cycle regulator
• T-cell acute lymphoblastic leukemia/t-cell lymphoblastic lymphoma (T-ALL/LBL)
• obesity
• metabolism

Article highlights

• Hematopoietic stem/progenitor cells lacking CDK6 protein or kinase activity are resistant to Notch-induced T-ALL

• Inhibition of CDK6 kinase activity with CDK4/6 inhibitors causes apoptosis of mouse/human T-ALL cells.

• Obese T-ALL patients have higher five-year mortality rates than non-obese patients.

• Loss of CDK6 is associated with a protection against obesity in rodent models and is associated with thinness in human.

• CDK4/6 inhibitors synergize with other drugs to enhance efficacy or conquer resistance

Declaration of interests

The authors have no 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 manuscript was supported by DOD (W81XWH1910301), a Tufts CTSI-Catalyst Awards (UL1 TR002544), and AG078484 to MG Hu.