Abstract 3424: Induction of prolonged early G1-arrest by CDK4/CDK6 inhibition reprograms cycling lymphoma cells for enhanced and sustained inhibition of PI3Kδ/AKT.
Authors: Chiron David , Martin Peter , Di Liberto Maurizio , Huang Xiangao , Ely Scott A. , Lannutti Brian J. , Leonard John P. , Mason Christopher E. , Chen-Kiang Selina 
Published: August 2014

The phosphatidylinositol-3-kinase (PI3K) signaling pathway is constitutively activated at a high frequency in cancer. Interest in evaluating the therapeutic utility of selective PI3K subunit inhibition has led to the development of potent PI3Kδ-specific inhibitors. Selective inhibition of PI3Kδ has now emerged as a promising therapy for chronic lymphocytic leukemia and indolent lymphomas. For aggressive non Hodgkin lymphoma such as mantle cell lymphoma (MCL), however, efficacy has been observed but duration of tumor control has been modest, encouraging development of mechanism-based combination therapy.

We hypothesize that induction of G1-cell cycle arrest may reprogram non-indolent lymphomas to PI3Kδ inhibition, and test this hypothesis in MCL based on the following: 1) aberrant cyclin D1 and CDK4 expression is the primary cause for unrestrained cell cycle progression and proliferation in MCL; 2) by induction of prolonged early G1 arrest (pG1) through selective inhibition of CDK4/CDK6, we have developed a novel strategy that both inhibits proliferation of tumor cells and sensitizes them to cytotoxic killing; and 3) induction of pG1 by CDK4/CDK6 inhibition has demonstrated encouraging clinical activity, with an excellent toxicity profile, in a phase I clinical trial in MCL.

Here we show in primary MCL cells (N=10) by whole transcriptome-sequencing (WTS) that mutations in coding regions are rare in Cyclin D1, CDK4 and other genes that control G1 cell cycle progression or in the PI3K/AKT signaling pathway. PI3Kδ is the predominant PI3K catalytic expressed in MCL cells. Selective inhibition of PI3Kδ transiently reduces AKT phosphorylation but does not inhibit the cell cycle in proliferating MCL cells, implying a potential mechanism for resistance. Induction of pG1 by CDK4/CDK6 inhibition amplifies and sustains PI3Kδ inhibition and induces robust apoptosis.

Validating the G1 cell cycle-dependence of PI3Kδ inhibition, all primary MCL cells tested are responsive to PI3Kδ inhibition when they cease to cycle in ex vivo in stromal co-culture. This loss of viability is further accelerated in pG1 induced by CDK4/CDK6 inhibition, despite the presence of cytokines and growth factors that are known to activate PI3K.

This study presents the first sequential combination of selective inhibition of CDK4/CDK6 with a selective partner, a PI3Kδ specific inhibitor, in primary human cancer cells and the first WTS-validated therapeutic strategy that leads to sensitization of MCL cells by cell cycle control. Our data demonstrate, for the first time, that the magnitude and duration of PI3K inhibition is G1 cell cycle-dependent, and suggest a strategy to sensitize proliferating lymphoma cells to selective PI3Kδ inhibition by induction of early G1-arrest through selective CDK4/CDK6 inhibition.

Citation Format: David Chiron, Peter Martin, Maurizio Di Liberto, Xiangao Huang, Scott A. Ely, Brian J. Lannutti, John P. Leonard, Christopher E. Mason, Selina Chen-Kiang. Induction of prolonged early G1-arrest by CDK4/CDK6 inhibition reprograms cycling lymphoma cells for enhanced and sustained inhibition of PI3Kδ/AKT. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3424. doi:10.1158/1538-7445.AM2013-3424

Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.