BRAF vs RAS oncogenes: are mutations of the same pathway equal? Differential signalling and therapeutic implications

Abstract

As the increased knowledge of tumour heterogeneity and genetic alterations progresses, it exemplifies the need for further personalized medicine in modern cancer management. Here, the similarities but also the differential effects of RAS and BRAF oncogenic signalling are examined and further implications in personalized cancer diagnosis and therapy are discussed. Redundant mechanisms mediated by the two oncogenes as well as differential regulation of signalling pathways and gene expression by RAS as compared to BRAF are addressed. The implications of RAS vs BRAF differential functions, in relevant tumour types including colorectal cancer, melanoma, lung cancer are discussed. Current therapeutic findings and future viewpoints concerning the exploitation of RAS-BRAF-pathway alterations for the development of novel therapeutics and efficient rational combinations, as well as companion tests for relevant markers of response will be evaluated. The concept that drug-resistant cells may also display drug dependency, such that altered dosing may prevent the emergence of lethal drug resistance posed a major therapy hindrance.

Figure 1. The Ras/Raf/MEK/ERK pathway and the Ras/PI3K/PTEN/mTOR pathway are activated by external factors such as growth factors and mitogens

Once RAS is turned on, it recruits and activates proteins necessary for the propagation of growth factor and other receptor signals, such as RAF and PI3K.

Figure 2. Mutant KRAS two way activation of the MAPK and PI3K pathway

Figure 3. Mutant KRAS can induce either BRAF/BRAF or BRAF-CRAF dimerization of wild type proteins

Figure 4. MAPK pathway activation in response to BRAF mutation

Figure 5. Mutant BRAF activation via protein dimerisation

Figure 6. RAS pathway inhibitors and resistance mechanisms

[160, 161, 180]. (A) Inhibitors of the key downstream effectors of RAS. All downstream RAS effectors are cytosolic protein kinases that form a tiered protein kinase cascade downstream of RAS. (B) The resistance mechanism against BRAF inhibitor vemurafenib (PLX4032).