Lung cancer protein structure revealed in key step in drug design

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Around 30,000 cases of lung cancer occur each year in Spain. KRAS oncogene mutations account for 10-15% of these cases, a subgroup against which there are still no effective therapies.

The groups of Mariano Barbacid at the Spanish National Cancer Research Center (CNIO) and Guillermo Montoya at the University of Copenhagen have succeeded in determining the structure of the RAF1 protein, a therapeutic target against cancers associated with KRAS oncogenes .

The results of this study, published in molecular cellhelps identify structural vulnerabilities in RAF1, a key step in designing drugs capable of destroying it.

The creation of RAF1 degraders is a realistic option to put these experimental results into clinical practice, and thus be able to fight these tumors with new therapeutic weapons in the not too distant future”, says Sara García-Alonso, CNIO researcher and co- lead author of the study.

One of the main challenges in oncology is the development of drugs against 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 pancreatic ductal adenocarcinoma.

Although KRAS oncogenes were already discovered by Mariano Barbacid’s group four decades ago, the first drug against them – Sotorasib, Amgen – was approved by the FDA only a year ago. As important as this milestone is, Sotorasib only works against 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 against 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, could 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 could 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 the development of drugs capable of degrading 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.”

Reference: García-Alonso S, Mesa P, Ovejero L de la P, et al. The structure of the RAF1-HSP90-CDC37 complex reveals the basis of RAF1 regulation. Mol Cell. 2022;0(0). do I: 10.1016/j.molcel.2022.08.012

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