title: Induction of prolonged early G1 arrest by CDK4/CDK6 inhibition reprograms lymphoma cells for durable PI3Kδ inhibition through PIK3IP1.
abstract: Phosphatidylinositol-3-kinase (PI3K) signaling is constitutive in most human cancers. Selective inhibition of PI3Kδ (p110δ) 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. PI3Kδ 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 PI3Kδ inhibition, which leads to robust apoptosis. Accordingly, inhibition of PI3Kδ 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.
authors.affiliation: Department of Pathology and Laboratory Medicine, Weill-Cornell Medical College, New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Chiron
authors.forename: Peter
authors.initials: P
authors.lastname: Martin
authors.forename: Maurizio
authors.initials: M
authors.lastname: Di Liberto
authors.forename: Xiangao
authors.initials: X
authors.lastname: Huang
authors.forename: Scott
authors.initials: S
authors.lastname: Ely
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Lannutti
authors.forename: John P
authors.initials: JP
authors.lastname: Leonard
authors.forename: Christopher E
authors.initials: CE
authors.lastname: Mason
authors.forename: Selina
authors.initials: S
authors.lastname: Chen-Kiang
mesh_terms: D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins; D008223:Lymphoma / Q000378:metabolism*; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D009154:Mutation / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D010879:Piperazines / Q000494:pharmacology; D011687:Purines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D052999:Quinazolinones / Q000494:pharmacology
chemical_list: D019938:Cyclin D1; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D019869:Phosphatidylinositol 3-Kinases; D010879:Piperazines; D011687:Purines; D011725:Pyridines; D052999:Quinazolinones; C530104:CCND1 protein, human; C521076:PIK3IP1 protein, human; C500026:palbociclib; C552946:idelalisib
keywords: CDK4; CDK6; GS-1101; PD 0332991; PI3Kα PIK3IP1; PI3Kδ; mantle cell lymphoma