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.