Cyclin-dependent kinase inhibitor therapy for hematologic malignancies

Abstract

INTRODUCTION Cyclin-dependent kinases (CDKs) regulate cell cycle progression. Certain CDKs (e.g., CDK7, CDK9) also control cellular transcription. Consequently, CDKs represent attractive targets for anti-cancer drug development, as their aberrant expression is common in diverse malignancies, and CDK inhibition can trigger apoptosis. CDK inhibition may be particularly successful in hematologic malignancies, which are more sensitive to inhibition of cell cycling and apoptosis induction. AREAS COVERED A number of CDK inhibitors, ranging from pan-CDK inhibitors such as flavopiridol (alvocidib) to highly selective inhibitors of specific CDKs (e.g., CDK4/6), such as PD0332991, that are currently in various phases of development, are profiled in this review. Flavopiridol induces cell cycle arrest, and globally represses transcription via CDK9 inhibition. The latter may represent its major mechanism of action via down-regulation of multiple short-lived proteins. In early phase trials, flavopiridol has shown encouraging efficacy across a wide spectrum of hematologic malignancies. Early results with dinaciclib and PD0332991 also appear promising. EXPERT OPINION In general, the anti-tumor efficacy of CDK inhibitor monotherapy is modest, and rational combinations are being explored, including those involving other targeted agents. While selective CDK4/6 inhibition might be effective against certain malignancies, broad spectrum CDK inhibition will likely be required for most cancers.

Flow sorting and exome sequencing reveal the oncogenome of primary Hodgkin and Reed-Sternberg cells

“…Some of these alterations have previously been described in hematologic and nonhematologic malignancies and are potentially therapeutically targetable (reviewed in Table 3). [35][36][37][38][39][40][41][42][43][44] Among the genes recurrently altered in cHL, some encode proteins that have been proposed to play a role in lymphomagenesis, although mutations in these genes have not been previously described in lymphoid malignancies. PIM kinases are overexpressed in chronic lymphocytic leukemia, mantle cell lymphoma, and multiple myeloma; and in vitro inhibition results in cellular toxicities.…”

Cyclin E1 Inhibition can Overcome Sorafenib Resistance in Hepatocellular Carcinoma Cells Through Mcl-1 Suppression

“…Our data support the use of CDK inhibitors in combination therapy for hepatocellular carcinoma. Pan-CDK inhibitors such as flavopiridol or dinaciclib may have better antitumor activity through both cell-cycle regulation and the suppression of the expression of antiapoptotic proteins, including Mcl-1, Bcl-XL, and XIAP (32,33). A potential concern about using pan-CDK inhibitors is the off-target adverse events.…”

Pro‐survival signal inhibition by CDK inhibitor dinaciclib in Chronic Lymphocytic Leukaemia

“…Despite their strong apoptotic effects on malignant B cells, the efficacy of CDK inhibitors as monotherapy has not been as successful as expected (Bose, et al 2013). Dinaciclib has only a 54% overall response rate in relapsed/refractory CLL patients and a tumour lysis syndrome is sometimes induced (Flynn, et al 2015).…”