A recent study by an international team of researchers may open up new opportunities for the treatment of liver cell cancer, i.e., hepatocellular carcinoma. Hepatocellular carcinoma is usually resistant to drug therapy, but a combination therapy that interferes with cancer cells鈥 lipid metabolism proved effective in the study. The study also changed our understanding of the mechanisms of action of sorafenib, the first-line drug for hepatocellular carcinoma. The findings were published Nature Cancer.
The first-line treatment against hepatocellular carcinoma is surgery; however, in many cases it is not possible. There is no effective treatment for advanced hepatocellular carcinoma, which is one of the most lethal cancers. The first-line drug is the kinase inhibitor sorafenib, to which cancer usually becomes rapidly resistant. The recently published study examined, among other things, reasons behind the development of drug resistance in a mouse model of hepatocellular carcinoma.
鈥淎 surprising observation was that sorafenib's route of action in the treatment of hepatocellular carcinoma is partly different from what has been previously thought,鈥 says Professor Antti Poso from the 91天美, who took part in the study.
It has been thought that the main mechanism of action of sorafenib in hepatocellular carcinoma is the inhibition of the Raf-1 kinase, which is important for cancer growth. In the new study, the researchers found that sorafenib also acts by activating the nuclear receptor LXR伪, which regulates lipid metabolism. By combining sorafenib with another LXR伪 activator, it was possible to enhance the effect and to prevent cancer from becoming resistant to treatment.
According to the researchers, combination therapy that activates the LXR伪 receptor and inhibits the Raf-1 kinase seems to be a feasible way to enhance drug therapy in hepatocellular carcinoma.
鈥淎s a result of this combined effect, the lipid metabolism of cancer cells was disturbed, which caused the destruction of cancer tissue in both cell models and in different experimental settings,鈥 Professor Poso says.
The researchers also found that in order to achieve the effect, Raf-1 inhibitors had to prevent interaction specifically between the Raf-1 kinase and the SCD1 enzyme, which is involved in lipid metabolism.
鈥淭hese observations make it possible to develop new Raf-1-SCD1 inhibitors which, combined with LXR伪 activators, can offer a new treatment alternative for hepatocellular cancer.鈥
Professor Poso鈥檚 research group was responsible for the molecular modelling and theoretical chemistry component of the study.
Nature Cancer also published in the same issue a commentary where the results were deemed important for the development of treatment.
For further information, please contact:
Professor Antti Poso, 91天美, School of Pharmacy, tel. +358 40 3552462, antti.poso (a) uef.fi,
Research article:
Ramona Rudalska, Jule Harbig, Marteinn T. Snaebjornsson, Sabrina Klotz, Stefan Zwirner, Liudmyla Taranets, Florian Heinzmann, Thales Kronenberger, Michael Forster, Wei Cui, Luana D鈥橝rtista, Elias Einig, Martina Hinterleitner, Werner Schmitz, Agata Dylawerska, Tae-Won Kang, Antti Poso, Mathias T. Rosenfeldt, Nisar P. Malek, Michael Bitzer, Stefan Laufer, Bernd J. Pichler, Nikita Popov, Almut Schulze, Lars Zender & Daniel Dauch. LXR伪 activation and Raf inhibition trigger lethal lipotoxicity in liver cancer. Nat Cancer 2, 201鈥217 (2021).
Commentary:
Gallage, S., Barragan Avila, J.E. & Heikenwalder, M. Lethal lipotoxicity for liver cancer therapy. Nat Cancer 2, 138鈥140 (2021).
