The structure of a key protein to create lung cancer drugs revealed

groups of Mariano Barbacid at the National Cancer Research Center (CNIO), and William Montoyafrom the University of Copenhagen, were able to determine the structure of the RAF1 protein, a therapeutic target against tumors associated with KRAS oncogenes.

This result, published in Molecular Cellallows the identification of structural vulnerabilities in RAF1, which makes it possible to design drugs capable of destroying it.

“The generation of RAF1 degraders represents 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”, he says. Sara Garcia-Alonsoresearcher at the CNIO and co-lead author of the work

The development of drugs against KRAS oncogenes is one of the main challenges in oncology. Those oncogenes —genes that, when mutated, cause cancer— are responsible for a quarter of all human tumors, including the three highest mortality tumor types: lung adenocarcinomacolorectal carcinoma and ductal adenocarcinoma of the pancreas.

Although KRAS oncogenes were discovered by Mariano Barbacid’s group four decades ago, the first drug against them —Sotorasib, Amgen— was only approved in the US a little over a year ago. Despite the importance of this milestone, the clinical impact of Sotorasib is limited, as it only acts against tumors that carry one of the multiple mutations present in KRAS oncogenes. Furthermore, patients treated with this drug develop resistance within a few months of treatment.

In addition to drug development against KRAS, one of the most active areas of research at the moment is identifying protein inhibitorssuch as RAF1, responsible for transmitting the oncogenic signals of KRAS.

In this sense, the Barbacid laboratory, using genetically modified mouse models that closely mimic human lung adenocarcinomas, showed four years ago that deletion of the RAF1 protein induced regression of most tumors without causing significant toxicity.

Purpose: to degrade the RAF1 protein

These observations generated enormous interest in finding drugs capable of degrading RAF1. published results Molecular Cell open a way to design RAF1 degraders that, alone or in combination with KRAS inhibitors, can generate a therapeutic effect in patients with KRAS oncogene-induced lung adenocarcinoma.

The determination of three-dimensional structure of RAF1 is a key step in this goal, as it exposes the parts of the protein to which a drug may be chemically bound and promotes its destruction by the cellular machinery (the cell has cleaning mechanisms responsible for the degradation of proteins that it considers defective or useless).

The main researchers responsible for this work were 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 that can degrade RAF1”, says García-Alonso.

Financing

The Barbacid group was funded mainly by the CRIS Contra o Cancro Foundation, the Spanish Association Against Cancer and the AXA Research Fund, as well as public funds from the Ministry of Science and Innovation and the European Research Council (ERC).