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.

Modulation of Ras/ERK and Phosphoinositide Signaling by Long-Chain n-3 PUFA in Breast Cancer and Their Potential Complementary Role in Combination with Targeted Drugs

“…Hyperactivation of the Ras/ERK signaling was observed in half of breast tumors [49,50] and has been associated with malignancy and poor prognosis in breast cancer patients [51,52,53]. Most of the components in the RAS/ERK signaling pathway are overexpressed in the breast [54], but, in most cases their overexpression has not been related to activating mutation of either RAS or BRAF, as happens in other types of cancers, such as melanoma [55].…”

Current and future molecular diagnostics in non-small-cell lung cancer

“…In NSCLC, the BRAF mutation frequency is approximately 2% [62]. The V600E mutation is the most common mutation, followed by V600K and V600R [63]. Several inhibitors can target the particular mutation and show different levels of success in other cancers.…”

“…Several inhibitors can target the particular mutation and show different levels of success in other cancers. Currently, the RAF kinase inhibitors Vemurafenib, Dabrafenib, and Sorafenib are studied in NSCLC with BRAF mutation [63].…”

¿Existen ventajas clínicas al evaluar el estado de los genes KRAS, NRAS, BRAF, PIK3CA, PTEN y HER2 en pacientes con cáncer colorrectal?

“…La proteína KRAS participa como una molécula efectora responsable de la transducción al núcleo de las señales de ligandos unidos al EGFR dentro de la vía de señalización MAPK (Mitogen-Activated Protein Kinase) y puede estar alterada en el cáncer colorrectal avanzado o metastásico (metastasic Colorectal Cancer, mCRC) 27 . La aparición de metástasis está favorecida por rasgos genéticos de la célula tumoral circulante y por un microambiente tisular favorable en el órgano blanco 28 .…”