One of the main challenges in oncology is the development of drugs once morest KRAS oncogenes. These oncogenes – genes that cause cancer when mutated – are responsible for a quarter of all human cancers, including the three types of tumors with the highest mortality rates: lung adenocarcinoma, colorectal carcinoma and ductal adenocarcinoma pancreatic.
Although KRAS oncogenes were already discovered by Mariano Barbacid’s group four decades ago, the first drug once morest them – Sotorasib, Amgen – was approved by the FDA only a year ago. As important as this milestone is, Sotorasib only works once morest tumors harboring one of the multiple mutations present in KRAS oncogenes and its clinical impact is therefore limited. In addition, patients treated with this drug develop resistance within a few months of treatment.
RAF1 and lung adenocarcinoma
Beyond the development of drugs once morest KRAS, one of the most active lines of research at present aims to identify protein inhibitors, such as RAF1, responsible for the transmission of KRAS oncogenic signals.
In this regard, the laboratory of Mariano Barbacid, using genetically modified mouse models that faithfully recapitulate human lung adenocarcinomas, demonstrated four years ago that the elimination of the RAF1 protein induced the regression of most tumors without effects significant toxins.
Target: degrade RAF1
These observations have generated enormous interest in finding drugs capable of degrading RAF1. The results published today in molecular cell open a window of opportunity to design RAF1 degraders that, alone or in combination with KRAS inhibitors, might generate a significant therapeutic effect in patients with KRAS oncogene-induced lung adenocarcinoma.
Determining the three-dimensional structure of RAF1 is a key step towards this goal, as it reveals the parts of the protein on which a drug might chemically anchor, and promotes its destruction by the cellular machinery (cells have that degrade defective or useless proteins).
The principal investigators responsible for this work are Sara García-Alonso, from the CNIO, and Pablo Mesa, from the Molecular and Structural Biology Group at the University of Copenhagen.
“The information provided by this study opens up a range of options for developing drugs that can degrade RAF1,” says García-Alonso. “A window of opportunity is now open to design RAF1 degraders with significant therapeutic effect in patients with KRAS oncogene-induced lung adenocarcinoma. »
Funding
Barbacid’s group was funded primarily by the CRIS Cancer Foundation, the Spanish Association Against Cancer (AECC) and the AXA Research Fund, as well as public funds from the Spanish Ministry of Science and the European Health Council. research (ERC). Sara García-Alonso is currently on a postdoctoral contract with the AECC.
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Materials provided by National Center for Oncological Research (CNIO). Note: Content may be edited for style and length.