Researchers clarify the role of the two isoforms of KRAS, the most common oncogene in humans


KRAS4A-induced lung carcinoma. Credit: CNIO

KRAS was one of the first oncogenes identified a few decades ago. It is among the most common drivers of cancer and its mutations can be detected in about 25 percent of human tumors. The development of KRAS inhibitors is therefore an extremely active line of research. So far, the effective results have been elusive, although there was no KRAS inhibitor until a month ago, when the FDA granted approval to Sotorasib.

KRAS encodes two , KRAS4A and KRAS4B, whose levels can vary between organs and embryonic stages. When KRAS mutates, both variants or isoforms are activated. However, some studies have focused on approaches to target only KRAS4B, as it is often found to be expressed at higher levels in tumors.

In this study, Matthias Drosten, Marina Salmón, and Guillem Paniagua of the Experimental Oncology Program, led by Mariano Barbacid at the CNIO, had a more fundamental goal: to understand how isoforms work separately. As stated in the document to be published in PNAS“The biological relevance of the expression of two isoforms has baffled researchers for decades.”

Lung cancer and metastasis

In principle, a basic research project, the Drosten and Salmon study produced results that were “a surprise”. Although KRAS4B is the dominant form a , the KRAS4A mutant is also oncogenic and is even more active.

In the words of the authors, “KRAS4AG12V alone, in the absence of KRAS4B, can induce and metastasis in 20 percent of individuals. Our results suggest that for therapies to be effective, the two KRAS isoforms must be targeted. “

KRAS genes in embryonic development

CNIO researchers created two models of genetically modified mice that lacked KRAS4B and expressed only the KRAS4A variant, with and without the G12V mutation (KRAS4AG12V).

In addition, the study explored the role of the two isoforms in embryonic development. One of them, KRAS4B, “is key after birth, as in the absence of this variant, mice cannot grow as a result of heart disease.”

The CNIO Experimental Oncology Group is a global organization studying KRAS-related cancers, with notable examples such as the elimination of lung tumors and advanced pancreatic tumors by inactivating RAF1 kinase in animal models.

Scientists discover mutations that make cancer resistant to KRAS-targeted therapies

More information:
Marina Salmón et al., “KRAS4A induces metastatic lung adenocarcinomas in vivo in the absence of the KRAS4B isoform.” PNAS (2021).

Citation: Researchers clarify the role of the two isoforms of KRAS, the most common oncogene in humans (2021, July 19) recovered on July 19, 2021 at -isoforms-kras-common -oncogene.html

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