Multi-kinase inhibition in ovarian cancer

Sorafenib (Nexavar) is a multi-kinase inhibitor that was developed as an inhibitor of RAF-1, in the ERK1/2 pathway, but which was subsequently shown to inhibit class III tyrosine kinase receptors. (1) More recently regorafenib (Stivarga) has been developed, which is a further fluorinated version of sorafenib with greater bioavailability and similar inhibitory properties against RAF-1/class III RTKs. (2) Some of the anti-tumor effects of sorafenib have been ascribed to anti-angiogenic actions of this agent on endothelial associated kinases such as VEGFR2. Other effects of sorafenib clearly have to be due to its effects on the inherent biology of the tumor cells themselves. For example, through various mechanisms sorafenib has been shown in the laboratory and the clinic to suppress expression of the protective protein MCL-1. (3) Sorafenib has also been linked to inhibition of STAT3, NFκB, and activation of the death receptor CD95. (4) Sorafenib is routinely dosed daily (400 mg BID) and 7 d after the start of dosing has a Cmax of ~21 μM with a nadir at 12 h of ~10 μM, and is a highly protein bound based on in vitro assays. (5) Despite this in vitro binding data sorafenib has profound in vivo effects on tumor cells in renal carcinoma and hepatocellular carcinoma patients; cells which are not per se addicted to high activity oncogene signals that are targets of sorafenib/regorafenib. Thus the precise stable bioavailable level of sorafenib/regorafenib in patient plasma is not known.