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

Hepatocytes are the foreign legionnaires in our body. They are exposed to various xenobiotics, which invigorates them and when transformed into malignant cells, renders them drug resistant. So far, treatment with the multikinase inhibitor sorafenib, which blocks Raf, vascular endothelial growth factor receptor and platelet-derived growth factor receptor signalling, is the only approved targeted therapy for advanced hepatocellular carcinoma (HCC). However, sorafenib extends the average life expectancy of patients only 2.8 months over the placebo,1 which offers room for improvement. 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 The history of palbociclib is tightly linked to the decipherment of G1 cell cycle checkpoint regulation that started in 1991 with the discovery of D-type cyclins. CDK4 and CDK6 were discovered soon thereafter. They bind physically to and are enzymatically activated by D-type cyclins, which leads to phosphorylation and inactivation of retinoblastoma (RB1), the key gatekeeper of G1/S transition. Given the importance RB1 in cancer development, pharmacists started to develop CDK4/6 inhibitors such as palbociclib (Pfizer), ribociclib (Novartis) and abemaciclib (Elli Lilly). However, early clinical trials with palbociclib monotherapy dampened the initial enthusiasm for this drug, although tumour regression was observed in some patients with liposarcoma. A breakthrough was achieved when palbociclib was combined with letrozole, an aromatase inhibitor, for the treatment of oestrogen receptor-positive breast …