They manage to determine the structure of the RAF1 protein, what could be key in the creation of new drugs Against the lung cancer.
Specifically, it It is a therapeutic target against the KRAS oncogene-associated tumors.
These oncogenes (genes that, when mutated, cause cancer) are responsible for a quarter of all human tumorsincluding the three tumor types with the highest mortality: lung adenocarcinoma, colorectal carcinoma and ductal adenocarcinoma of the pancreas.
Although KRAS oncogenes were discovered by the Barbacid group four decades agothe first drug against them (sotorasib, from Amgen) alone has been approved in the United States just over a year ago.
Despite this, the clinical impact of sotorasib is limitedbecause it only works against tumors carrying one of multiple mutations present in KRAS oncogenes.
Furthermore, patients treated with this drug develop resistance within a few months of treatment.
RAF1 AND ADENOCARCINOMA OF THE LUNG
Beyond the development of drugs against KRAS, one of The most active areas of research at this time consist in identifying protein inhibitors, such as RAF1, responsible for transmitting KRAS oncogenic signals.
In this sense, the laboratory of Mariano Barbacid, using genetically modified mouse models that faithfully reproduce the human lung adenocarcinomasshowed four years ago that the deletion of RAF1 protein induced regression of most tumors without cause significant toxicities.
OBJECTIVE: DEGRADE RAF1
These observations have generated enormous interest in obtaining pharmaceuticals capable of degrading RAF1. The results, published in the journal ‘Molecular Cell‘, open a window of opportunity to design RAF1 degraders that, either alone or in combination with KRAS inhibitors, can generate a significant effect therapeutic in patients with lung adenocarcinoma induced by KRAS oncogenes.
Determining the three-dimensional structure of RAF1 is a key step in that goal, because it reveals the parts of the protein that a drug could target. chemically anchorand promote its destruction by the cellular machinery (the cell has cleaning mechanisms that are responsible for degrading the proteins that considered defective or useless).
“The information provided by this study opens up a range of options for developing drugs that manage to degrade RAF1”, says researcher Sara García-Alonso, from the CNIO. “It opens now a window of opportunity to design RAF1 degraders with an important therapeutic effect in patients with lung adenocarcinoma induced by KRAS oncogenes”, he adds.