ABSTRACT
BACKGROUND:
Mantle cell lymphoma (MCL) is a chronically relapsing
malignancy with deregulated
cell cycle progression. We analyzed
efficacy, mode of action, and predictive markers of susceptibility to palbociclib, an approved CDK 4/6 inhibitor, and its combination with venetoclax, a BCL2 inhibitor.
METHODS:
A panel of nine MCL
cell lines were used for
in vitro experiments. Four
patient derived
xenografts (PDX) obtained from
patients with
chemotherapy and ibrutinib-refractory MCL were used for in vivo proof-of-concept studies. Changes of the
mitochondrial membrane potential, energy-
metabolic pathways, AKT activity, and pro-apoptotic priming of MCL
cells were evaluated by JC-1
staining,
Seahorse XF analyser, genetically encoded fluorescent AKT reporter, and BH3 profiling, respectively. MCL
clones with
gene knockout or transgenic (over)expression of CDKN2A, MYC, CDK4, and RB1 were used to estimate impact of these aberrations on
sensitivity to palbociclib, and venetoclax.
RESULTS:
Co-targeting MCL
cells with palbociclib and venetoclax induced cytotoxic synergy
in vitro and in vivo. Molecular mechanisms responsible for the observed
synthetic lethality comprised palbociclib-mediated
downregulation of anti-apoptotic MCL1, increased levels of proapoptotic BIM bound on both BCL2, and BCL-XL and increased pro-apoptotic priming of MCL
cells mediated by BCL2-independent mechanisms, predominantly palbociclib-triggered metabolic and mitochondrial stress. Loss of RB1 resulted in palbociclib resistance, while deletion of CDKN2A or overexpression of CDK4, and
MYC genes did not change
sensitivity to palbociclib.
CONCLUSIONS:
Our data strongly support investigation of the
chemotherapy-free palbociclib and venetoclax combination as an innovative
treatment strategy for post-ibrutinib MCL
patients without RB1 deletion.
