Abstract 3095: Longitudinal integrative whole transcriptome and exome sequencing identifies genes that reprogram lymphoma cells for clinical response to CDK4/6 inhibition in combination therapy
Authors: Di Liberto Maurizio , Martin Peter , Chiron David , Vijay Priyanka , Huang Xiangao , Blecua Pedro , Ely Scott , Elemento Olivier , Leonard John P. , Mason Christopher E. , Chen-Kiang Selina 
Published: August 2015

CDK4 and CDK6 drive cell cycle progression through early G1 and are frequently deregulated in human cancer. The selective inhibitor palbociclib (PD 0332991) demonstrated exciting clinical efficacy in diverse human cancers, notably in metastatic breast cancer where it more than doubled the progression free survival of patients treated with letrozole. In mantle cell lymphoma (MCL), deregulated CDK4 and cyclin D1 expression underlies unrestrained proliferation and disease progression. In a phase I clinical trial in recurrent MCL, we showed that palbociclib produced a durable clinical response. However, the mechanism that discriminates sensitivity from resistance to targeting CDK4/6 remains obscure.

To address this question, we demonstrated that 1) inhibition of CDK4/6 leads to early G1 arrest that requires Rb, the CDK4/6 substrate; 2) prolonged early G1 arrest (pG1) sensitizes Rb+ cancer cells to killing by diverse clinically-relevant agents; and 3) pG1 sensitization stems from continuous expression of genes scheduled for early G1 only. This sensitization is exacerbated in synchronous progression to S phase (pG1-S) after palbociclib withdrawal, due to incomplete restoration of cell cycle-coupled gene expression. In a hypothesis-driven phase Ib clinical trial we further showed that palbociclib induces pG1 and sensitizes MCL cells to the proteasome inhibitor bortezomib. At the optimal dose of palbociclib, only one in 6 patients progressed, and 4 patients had a durable responses including a complete remission for &gt;800 days.

Longitudinal integrative whole transcriptome and whole exome sequencing of tumor cells from serial lymph node biopsies demonstrated that cell cycle control by palbociclib is initially intact in Rb+ MCL but is insufficient to predict clinical response. Palbociclib induced pG1 in all patients initially regardless of the subsequent clinical response or patient-specific copy number variation or mutation (ATM, p53). As expected, pG1 maintained the expression of cell cycle genes programmed for early G1 and suppressed those scheduled for other phases, and this was reversible upon release of the early G1 block.

However, expressing only genes scheduled for early G1 led to an imbalance in gene expression. Of the 1483 genes suppressed in pG1 compared with the baseline in Responders (Rs) (N = 4), 5 were up-regulated in Non-Responders (NRs) (N = 3); 11 of the 2041 genes up-regulated in pG1 in R were suppressed in NR. These oppositely expressed genes are involved in redox stress and metabolism based on functional analysis, suggesting a role for cell cycle-coupled metabolic imbalance in differential clinical response to targeting CDK4/6. Further validation of these candidate genes in the context of clinical response should advance the mechanism for therapeutic targeting of CDK4/6 as well as genome-based therapy and patient stratification.

Citation Format: Maurizio Di Liberto, Peter Martin, David Chiron, Priyanka Vijay, Xiangao Huang, Pedro Blecua, Scott Ely, Olivier Elemento, John P. Leonard, Christopher E. Mason, Selina Chen-Kiang. Longitudinal integrative whole transcriptome and exome sequencing identifies genes that reprogram lymphoma cells for clinical response to CDK4/6 inhibition in combination therapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3095. doi:10.1158/1538-7445.AM2015-3095