Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma

Abstract

ObjectiveAdvanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC.DesignThe effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses.ResultsPalbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of ‘RB1 loss of function’ was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival.ConclusionsPalbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.

The CDK4/6 inhibitor palbociclib synergizes with irinotecan to promote colorectal cancer cell death under hypoxia

“…Single agent palbociclib-treated mice showed a remarkable reduction in tumor volume, indicating that palbociclib treatment can be effective in liver tumors in vivo. 24 Our data indicates that palbociclib promotes apoptosis at 10 mM regardless of the presence of the presence of hypoxia ( Fig. 1 and 2).…”

“…Moreover, palbociclib-treated mice showed a remarkable reduction in tumor volume, indicating that palbociclib treatment can be effective against liver tumors in vivo. 24 These findings suggest that the anti-tumor effects and mechanisms of palbociclib could be more complicated than the primary CDK inhibitory activities. To further investigate how palbociclib may affect cell viability in CRC, cell death was evaluated by DNA fragment analysis (sub-G1 analysis).…”

Berberine-induced Inactivation of Signal Transducer and Activator of Transcription 5 Signaling Promotes Male-specific Expression of a Bile Acid Uptake Transporter

“…11995081) or PRMI-1640 medium (Gibco, catalog no. A1049101) as previously described (40). The cells were seeded into 6-well plates (3 ϫ 10 5 /well) or chamber slides (1.0 ϫ 10 5 /chamber) and allowed to adhere for 16 -24 h before BBR treatment.…”

CDK4/6 inhibition and sorafenib: a ménage à deux in HCC therapy?

“…Unfortunately, several other drugs and combinatorial therapies, such as sorafenib plus erlotinib failed in clinical trials 1 2. In this issue of Gut , Bollard et al 3 tested the combination of sorafenib with palbociclib in preclinical HCC mouse models. Palbociclib (or PD0332991) is a reversible and orally bioavailable low-molecular-weight cyclin-dependent kinase (CDK)4/6 inhibitor without significant off-target effects 4.…”

“…Senescent cancer cells readily acquire a senescence-associated secretory phenotype, which is characterised by cytokine production and attraction of cytotoxic immune cells that contribute to tumour cell killing 6. Bollard et al 3 treated 15 HCC cell lines with palbociclib to assess cellular responses. Hep3B cells, which harbour a mutation in RB1, did not respond with cell cycle arrest as demonstrated previously 7.…”