Why does sorafenib work in HCC but sunitinib does not?
That was the question from a reader that greeted me in my inbox recently, it’s a good point. Sorafenib has received FDA approval in this indication, while Pfizer terminated their phase III trial of sunitinib in HCC for futility last year.
At first, I couldn’t remember the subtle differences between them, since they both inhibit VEGF and PDGF, although sunitinib also inhibits KIT, until a friend reminded that sorafenib also targets RAF. On checking out the IC50 values of several multi-kinase TKIs, it turned out to be true, good catch:
In addition, there was a paper just published from Nagai et al., (2011) in Molecular Cancer Therapeutics, which demonstrated sorafenib inhibits the hepatocyte growth factor (HGF) mediated epithelial mesenchymal transition (EMT) in hepatocellular carcinoma (HCC). EMT is a key developmental program that is often activated during cancer invasion and metastasis. It is a highly complex area that is receiving a lot of research attention at the moment.
Nagai et al., essentially demonstrated that:
“Sorafenib and the MEK inhibitor U0126 markedly inhibited the HGF-induced morphologic changes, SNAI1 upregulation, and cadherin switching, whereas the PI3 kinase inhibitor wortmannin did not.
Collectively, these findings indicate that sorafenib downregulates SNAI1 expression by inhibiting mitogen-activated protein kinase (MAPK) signaling, thereby inhibiting the EMT in HCC cells.”
If we look at the potential pathway, it would look like this:
Based on these findings, it would be interesting to find out whether adding a MEK inhibitor to sorafenib would improve efficacy further to cut off feedback loops.
On checking out the clinical trials database, I found two trials either ongoing or about to begin enrolling with sorafenib and AZD6244 (ARRY 142886), a MEK inhibitor from AstraZeneca/Array Pharma. The former should have data emerging soon, if it hasn’t already done so. I think EMT is a fertile area of research where we may see more science and emerging this year.
References:
Nagai, T., Arao, T., Furuta, K., Sakai, K., Kudo, K., Kaneda, H., Tamura, D., Aomatsu, K., Kimura, H., Fujita, Y., Matsumoto, K., Saijo, N., Kudo, M., & Nishio, K. (2011). Sorafenib Inhibits the Hepatocyte Growth Factor-Mediated Epithelial Mesenchymal Transition in Hepatocellular Carcinoma Molecular Cancer Therapeutics, 10 (1), 169-177 DOI: 10.1158/1535-7163.MCT-10-0544