Targeting CDK4/6 in mantle cell lymphoma

Abstract

Targeting the cell cycle represents a rational approach to mantle cell lymphoma (MCL) therapy, as aberrant expression of cyclin D1 and dysregulation of CDK4 underlie cell cycle progression and proliferation of MCL cells. Although cell cycle cancer therapy was historically ineffective due to a lack of selective and effective drugs, this landscape changed with the advent of selective and potent small-molecule oral CDK4/6 inhibitors. Here, we review the anti-tumor activities and clinical data of selective CDK4/6 inhibitors in MCL. We summarize the known mechanism of action of palbociclib, the most specific CDK4/6 inhibitor to date, and the strategy to leverage this specificity to reprogram MCL for a deeper and more durable clinical response to partner drugs. We also discuss integrative longitudinal functional genomics as a strategy to discover tumor-intrinsic genomic biomarkers and tumor-immune interactions that potentially contribute to the clinical response to palbociclib in combination therapy for MCL. Understanding the genomic basis for targeting CDK4/6 and the mechanisms of action and resistance in MCL may advance personalized therapy for MCL and shed light on drug resistance in other cancers.

Keywords: CDK4 inhibitor; CDK6 inhibitor; Mantle cell lymphoma; ibrutinib; palbociclib.

Figure 1

A schema of cell cycle progression and induction of early G1 cell cycle arrest through CDK4/6 inhibition. TK1, thymidine kinase; PCNA, proliferating cell nuclear antigen; CDK, cyclin-dependent kinase.

Figure 2

CDK4/6 inhibitors and model of imbalanced gene expression in cell cycle. (A) Three oral small-molecule reversible CDK4/6 inhibitors that have been approved by the FDA for breast cancer treatment. (B) Model for reversible induction of prolonged cell cycle arrest in early G1 (pG1) by inhibition of CDK4/CDK6 with palbociclib and synchronous S phase entry after the release from pG1 (pG1-S). Rb, retinoblastoma protein; CDK, cyclin-dependent kinase.

Figure 3

Whole transcriptome sequencing (WTS) analysis of indicated genes in normal peripheral B cells (PBCs) (n=6) and primary MCL cells from patients (n=73). MCL, mantle cell lymphoma.

Figure 4

pG1 sensitizes resistant BTK^WT MCL cells to ibrutinib [reproduced from reference (21) with permission]. (A) Schema for sequential incubation with PD 0332991 (palbociclib, 0.3 μmol/L) and ibrutinib (left). The total viable cells (×20,000 cells/mL) at 48 and 96 hours of ibrutinib treatment in 4 MCL cell lines (1 μmol/L for JEKO-1, MAVER-1 and MINO and 0.1 μmol/L for SP53) were determined (right). (B) Immunoblotting of activated BTK (pY223) and total BTK, activated AKT (pS473) and total AKT proteins in JEKO-1 cells cultured in the presence or absence of PD 0332991 (0.3 μmol/L) for 24 hours before addition of goat antihuman IgM (α-IgM, 5 μg/mL) to enhance B cell receptor signaling and ibrutinib (1 μmol/L) for 24 hours. pG1, prolonged early G1 arrest; MCL, mantle cell lymphoma.