Things are getting KRASy in Spanish science this week as two major papers debut new insight regarding the activity of the cancer-associated mutation KRAS.
First, in an article published in Nature, a potential drug interaction site on the KRAS protein was mapped out by a research group from The Barcelona Institute of Science and Technology.
A three-dimensional image showing the human protein KRAS (blue) interacting with RAF1 (yellow), one of its main partners. The blue-to-red colour gradient indicates increasing potential for allosteric effects. Weng, Faure and Escobedo/Centro de Regulación Genómica
Second, scientists at the Biomedical Research Institute of Murcia, Spain, have unveiled promising KRAS findings that could revolutionize the treatment landscape for Chronic Myelomonocytic Leukemia (CMML) and many other cancers. Published in Cell Reports Medicine and first-authored by Laura Hurtado-Navarro and Ernesto Jose Cuenca-Zamora, the Murcia group has uncovered a novel approach to quelling rampant inflammation in CMML patients.
The KRAS mutation, a prevalent variant of the RAS gene, is particularly notorious in various cancers, including tumors of the pancreas and colorectum. Research has implicated RAS mutations in 20-30% of all human cancers, with CMML showing RAS mutations in 7-22% of cases.
RAS mutations disrupt its protein's convoluted signaling pathway, preventing it from assuming its inactive state. When stuck in the "on" position, the RAS protein propels cell proliferation and survival but also causes the debilitating clinical features of CMML— the failure of blood cells to mature (myelodysplastic syndromes) and the overproduction of red and white blood cells or platelets (myeloproliferative neoplasms).
The study delved deep down the out-of-control singling pathway of KRAS to explore the dysfunction it begets. The researchers focused on a key player in the inflammatory landscape, NLRP3. NLRP3 is a member of an inflammasome, a multiprotein complex that signals the presence of pathogens or cellular damage. NLRP3 activity is implicated in diseases ranging from Alzheimer's to diabetes.
It turns out that the KRAS mutation activates NLRP3 and triggers the release of proinflammatory cytokines like IL-1beta, causes punctures in the cell membrane and ultimately leads to cell death.
Taking a bold step forward, the scientists explored the potential of an IL-1beta inhibitor called anakinra to alleviate the debilitating effects of CMML patients with the KRAS mutation. In a groundbreaking revelation, IL-1beta inhibitor treatment led to significant clinical improvements.
Anakinra treatment improved white blood cell production and positively impacted the weight of CMML patients with KRAS mutation, leading to significant clinical improvements.
Further experiments using human samples demonstrated that anakinra successfully decreased NLRP3 inflammasome activity, offering a glimmer of hope for CMML patients grappling with mutated KRAS.
The study's implications extend beyond CMML, as KRAS mutations are prevalent in various cancers. Anakinra and other IL-1beta blockers emerge as a viable strategy to improve clinical outcomes and control NLRP3 inflammasome activation in a spectrum of cancers with KRAS mutations.
Sources: International Journal of Molecular Sciences, Cell Reports Medicine, Nature