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’ 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.
“A surprising observation was that sorafenib's route of action in the treatment of hepatocellular carcinoma is partly different from what has been previously thought,” says Professor Antti Poso from the University of Eastern Finland, 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 LXRα, which regulates lipid metabolism. By combining sorafenib with another LXRα 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 LXRα receptor and inhibits the Raf-1 kinase seems to be a feasible way to enhance drug therapy in hepatocellular carcinoma.
“As 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,” 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.
“These observations make it possible to develop new Raf-1-SCD1 inhibitors which, combined with LXRα activators, can offer a new treatment alternative for hepatocellular cancer.”
Professor Poso’s 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, University of Eastern Finland, School of Pharmacy, tel. +358 40 3552462, antti.poso (a) uef.fi, https://uefconnect.uef.fi/en/person/antti.poso/
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’Artista, 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. LXRα activation and Raf inhibition trigger lethal lipotoxicity in liver cancer. Nat Cancer 2, 201–217 (2021). https://doi.org/10.1038/s43018-020-00168-3
Commentary:
Gallage, S., Barragan Avila, J.E. & Heikenwalder, M. Lethal lipotoxicity for liver cancer therapy. Nat Cancer 2, 138–140 (2021). https://doi.org/10.1038/s43018-021-00175-y
