A study published in Cancer Cell by researchers of the Molecular Oncology Program at the Spanish National Cancer Research Centre (CNIO) shows how the elimination of the c-Raf kinase by genetic manipulation causes the regression of Kras oncogene-driven advanced lung tumours in a genetically designed mouse model that faithfully reproduces the natural history of this tumour. It has also been shown that the elimination of the c-Raf protein produces very tolerable toxic effects. This opens a new possibility for the development of therapies against tumours for which there are still no selective medicines and which therefore must be treated with cytotoxic drugs, that, as it is known, are not effective and produce abundant side effects.
One in four human solid tumours harbours mutations in KRAS, some, such as adenocarcinomas of the pancreas, lung and colon with very poor prognosis. The alteration of this gene directly and indirectly affects cell proliferation and differentiation through the activation of multiple signalling pathways, key phenomena in tumour development. However, there are no approved compounds in the clinic that selectively attack these pathways present in these carcinomas.
Blocking these oncogenic signalling pathways without affecting normal homeostasis is "one of the greatest challenges of precision medicine," the authors note. In the case of KRAS signalling, the attempts made to date with the inhibition of the MEK and ERK kinases, although effective in preventing the development of the tumour, induce unacceptable toxicity.
Lung cancer is the leading cause of cancer-related deaths worldwide, accounting for an estimated 1.8 million new cases per year. Non-small-cell lung carcinoma (NSCLC), which is the most frequent subtype of lung cancer, also carries mutations in KRAS in up to 30% of the cases. Additionally, the 5-year survival rate for lung cancer remains below 15%, thus underscoring the urgent need to improve the current treatment for these cancer patients.
In this new work, researchers have genetically engineered a new mouse model that has allowed c-Raf to be eliminated not only in advanced lung tumours but systemically throughout the body of the animal. Thus being able to predict the possible toxicity of drugs that block the activity of c-Raf may have: "that is, a scenario that makes it possible to translate these results in the future to the clinic".
As explained by Monica Musteanu, one of the work´s main authors, this study shows that the elimination of c-Raf "provides a significant therapeutic benefit that results in the regression of most tumours with very acceptable levels of toxicity". However, the authors warn that in this study, the therapeutic effect observed requires the elimination of the protein, something that at the moment is not possible to achieve by pharmacological strategies. Since c-Raf is a protein kinase, in principal the results described in this study could be validated by using selective inhibitors of this enzyme´s activity. In fact, the main priority of the authors at this time is to determine to what extent the therapeutic activity observed depends on the c-Raf kinase activity. The results that derive from these ongoing studies will serve to define what pharmacological strategy may be applied in the future to treat cancer patients.