KRAS is a common type of oncogene and is involved in at least one-fifth of all human cancers. Kras mutations cause 32% of lung tumors and 96% of pancreatic tumors. However, after more than 30 years of research, there is still no effective treatment strategy for this oncogene. For this reason, many studies have been conducted to try to identify other molecules that show therapeutic activity along the Kras Signaling Pathway. Faced with this challenge, researchers from the Experimental Tumor Group of the Spanish National Cancer Research Center (CNIO) found that the inactivation of CDK4 and RAF1 genes would lead to complete remission of 25% of lung tumors induced in mice with the KRAS gene mutation. This discovery has recently been published in PNAS.

In this study, the CNIO team explored a method that involves inactivating two genes in the KRAS signaling pathway: CDK4 and RAF1. Even so, as often found in clinical practice, a certain percentage of tumors can survive without CDK4 and RAF1. However, the researchers further determined the molecular mechanism that triggers this drug resistance and prevents tumor remission-the activation of the PI3K pathway, and the silencing of several Tumor Suppressor Genes through methylation. Lead author Laura de Esteban explains: “Both mechanisms can be therapeutically neutralized: on the one hand, PI3K inhibitors are used, and on the other hand, tumor suppressor genes are reactivated by selective demethylation.”

To conduct this research, the CNIO team used a mouse model that can accurately reproduce human diseases and induce aggressive lung tumors by activating the KRAS oncogene and inactivating the p53 tumor suppressor gene.

These findings provide enlightenment for the development of new therapies for tumors with KRAS mutations and indicate the importance of developing inhibitors specifically for RAF1. In addition, the author also pointed out that another research area to be carried out in the future is the study of multiple drug resistance pathways that may appear after inactivating the therapeutic target.

Reference

Laura Esteban-Burgos et al. Tumor regression and resistance mechanisms upon CDK4 and RAF1 inactivation in KRAS/P53 mutant lung adenocarcinomas. PNAS (2020). DOI: 10.1073/pnas.2002520117