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Induction of Prolonged Early G1 Arrest by CDK4/CDK6 Inhibition Reprograms Lymphoma Cells for Durable PI3Kδ Inhibition Through PIK3IP1

ABSTRACT: The RNA-seq data presented in this study include libraries from Mantle Cell Lymphoma (MCL) tumor cells of 4 patients, Peripheral Blood B Cells from 3 healthy volunteers and JEKO-1 MCL cell lines

ORGANISM(S): Homo sapiens

PROVIDER: GSE46846 | GEO | 2018/05/14

REPOSITORIES: GEO

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Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3K? inhibition through PIK3IP1.

Project description:Phosphatidylinositol-3-kinase (PI3K) signaling is constitutive in most human cancers. Selective inhibition of PI3K? (p110?) by GS-1101 has emerged as a promising therapy in chronic lymphocytic leukemia and indolent lymphomas. In aggressive non-Hodgkin lymphomas such as mantle cell lymphoma (MCL), however, efficacy has been observed, but the extent and duration of tumor control is modest. To determine if tumor killing by GS-1101 is cell cycle-dependent, we show in primary MCL cells by whole-transcriptome sequencing that, despite aberrant expression and recurrent mutations in Cyclin D1, mutations are rare in coding regions of CDK4, RB1 and other genes that control G1-S cell cycle progression or PI3K/AKT signaling. PI3K? is the predominant PI3K catalytic subunit expressed, and inhibition by GS-1101 transiently inhibits AKT phosphorylation but not proliferation in MCL cells. Induction of prolonged early G1-arrest (pG1) by selective inhibition of CDK4/CDK6 with PD 0332991 amplifies and sustains PI3K? inhibition, which leads to robust apoptosis. Accordingly, inhibition of PI3K? induces apoptosis of primary MCL tumor cells once they have ceased to cycle ex vivo, and this killing is enhanced by PD 0332991 inhibition of CDK4/CDK6. PIK3IP1, a negative PI3K regulator, appears to mediate pG1 sensitization to PI3K inhibition; it is markedly reduced in MCL tumor cells compared with normal peripheral B cells, profoundly induced in pG1 and required for pG1 sensitization to GS-1101. Thus, the magnitude and duration of PI3K inhibition and tumor killing by GS-1101 is pG1-dependent, suggesting induction of pG1 by CDK4/CDK6 inhibition as a strategy to sensitize proliferating lymphoma cells to PI3K inhibition.

| S-EPMC3735703 | biostudies-literature

Prolonged halting of gene expression in early G1 arrest by inhibition of CDK4/CDK6 reprograms myeloma cells for cytotoxic killing

Project description:By selective and reversible inhibition of CDK4/CDK6, we have developed a strategy to both inhibit proliferation and enhance cytotoxic killing of cancer cells. Induction of prolonged early-G1 arrest (pG1) by CDK4/CDK6 inhibition halts gene expression in early-G1 and prevents expression of genes programmed for other cell cycle phases. S-phase synchronization upon removal of the early-G1 block (pG1-S) fails to completely restore scheduled gene expression. Consequently, coordinate loss of IRF4 and gain of Bim and Noxa expression sensitize myeloma tumor cells to bortezomib-induced apoptosis in pG1 and more profoundly in pG1-S in vitro. Induction of pG1 and pG1-S by CDK4/CDK6 inhibition augments tumor-specific bortezomib killing in myeloma xenografts. Inhibition of CDK4/CDK6 in combination therapy thus represents a novel mechanism-based cancer therapy. PD 0332991 (PD) is the only known specific and reversible CDK4/CDK6 inhibitor. Gene expression was measured in myeloma MM1.S cells treated with PD (0.25 uM) in triplicate for 12, 24 or 36 h, or in cells released from G1, induced by 24hPD, for 4 or 18 h.

2012-04-06 | E-GEOD-35728 | biostudies-arrayexpress

Prolonged halting of gene expression in early G1 arrest by inhibition of CDK4/CDK6 reprograms myeloma cells for cytotoxic killing

2012-04-07 | GSE35728 | GEO

A defect of the INK4-Cdk4 checkpoint and c-myc collaborate in blastoid mantle cell lymphoma (MCL)-like lymphoma formation in mice

Project description:Mantle cell lymphoma (MCL) is a B cell malignancy characterized by a monoclonal proliferation of lymphocytes with co-expression of CD5, CD43 but not CD23. Typical MCL are associated with cyclin D1 overexpression, and blastoid MCL variants are associated with c-myc translocations. We have developed a murine model of MCL-like lymphoma by crossing Cdk4R24C mice with c-myc-3’RR transgenic mice. Cdk4R24C mice is a knock-in strain that express a Cdk4 protein resistant to inhibition by p16INK4a and other INK4 family members. Breeding Cdk4R24C mice with c-myc-3’RR transgenic mice prone to develop aggressive Burkitt lymphoma-like lymphoma leads in c-myc/Cdk4R24C mice to development of clonal blastoid MCL-like lymphoma. A defect of the INK4-Cdk4 checkpoint can participate to lymphomagenesis in conjunction with additional alterations of cell cycle control, a situation which might be reminiscent of the development of human blastoid MCL. B splenocytes from 4 c-myc/Cdk4(R24C) lymphoma mice and 4 wt mice were investigated.

2012-02-01 | E-GEOD-32230 | biostudies-arrayexpress

Cell Cycle Reprogramming for PI3K Inhibition Overrides Relapse-Specific C481S BTK Mutation Revealed by Longitudinal Functional Genomics in Mantle Cell Lymphoma

Project description:The RNA-seq data presented in this study include libraries from Mantle Cell Lymphoma (MCL) tumor cells sequentially obtained from patients

2017-02-25 | GSE55405 | GEO

The BTK Inhibitor CC-292 shows activity in Mantle Cell Lymphoma and synergizes with Lenalidomide and NIK Inhibitors depending on NFκB mutational status

Project description:Mantle Cell lymphoma (MCL) were treated with the BTK inhibitor 1mM CC-292 for 48h We used microarrays to uncover the mechanisms underlying CC-292 activity in Mantle Cell lymphoma (MCL)

2017-09-01 | GSE94328 | GEO

A defect of the INK4-Cdk4 checkpoint and c-myc collaborate in blastoid mantle cell lymphoma (MCL)-like lymphoma formation in mice

2012-02-01 | GSE32230 | GEO

Gene expression of mantle cell lymphoma-initiating cells from primary tumor samples

2014-08-02 | GSE60023 | GEO

Gene expression of mantle cell lymphoma-initiating cells from primary tumor samples

Project description:In this study we compared the expression of 30215 genes in mantle cell lymphoma-initiating cells (MCL-ICs) with mantle cell lymphoma-non-initiating cells (MCL-non-ICs) and B-cells from healthy donor Three samples each of MCL-ICs and MCL-non-ICs were isolated from aphresis of 3 mantle cell lymphoma primary patient samples and 2 samples of CD19+ Bcells isolated from buffy coats of healthy donor Microarray include both coding and non-coding transcripts but only mRNA coding transcript were included in this study.

2014-08-02 | E-GEOD-60023 | biostudies-arrayexpress

Dual CDK4/CDK6 inhibition induces cell-cycle arrest and senescence in neuroblastoma.

Project description:Neuroblastoma is a pediatric cancer that continues to exact significant morbidity and mortality. Recently, a number of cell-cycle proteins, particularly those within the Cyclin D/CDK4/CDK6/RB network, have been shown to exert oncogenic roles in neuroblastoma, suggesting that their therapeutic exploitation might improve patient outcomes.We evaluated the effect of dual CDK4/CDK6 inhibition on neuroblastoma viability using LEE011 (Novartis Oncology), a highly specific CDK4/6 inhibitor.Treatment with LEE011 significantly reduced proliferation in 12 of 17 human neuroblastoma-derived cell lines by inducing cytostasis at nanomolar concentrations (mean IC50 = 307 ± 68 nmol/L in sensitive lines). LEE011 caused cell-cycle arrest and cellular senescence that was attributed to dose-dependent decreases in phosphorylated RB and FOXM1, respectively. In addition, responsiveness of neuroblastoma xenografts to LEE011 translated to the in vivo setting in that there was a direct correlation of in vitro IC50 values with degree of subcutaneous xenograft growth delay. Although our data indicate that neuroblastomas sensitive to LEE011 were more likely to contain genomic amplification of MYCN (P = 0.01), the identification of additional clinically accessible biomarkers is of high importance.Taken together, our data show that LEE011 is active in a large subset of neuroblastoma cell line and xenograft models, and supports the clinical development of this CDK4/6 inhibitor as a therapy for patients with this disease. Clin Cancer Res; 19(22); 6173-82. ©2013 AACR.

| S-EPMC3844928 | biostudies-literature

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