Diverse Mechanisms of BRAF Inhibitor Resistance in Melanoma Identified in Clinical and Preclinical Studies

Conclusion Although treatment with BRAF inhibitors provides rapid response in most patients, treatment resistance persists. The few clinical studies of BRAF inhibitor resistance in patients indicate that genetic alterations that activate MAPK/Erk make up half of resistance mechanisms. Preclinical studies of BRAF inhibitor resistance in melanoma support the mechanisms observed in patients and indicate that the development of resistance is more complex than single mutations. In vitro models may be very helpful in studying mechanisms in the other half of patients with no known genetic driver of BRAF inhibitor resistance. Overall, BRAF inhibitor resistance depends on oncogenic signaling through reactivation of MAPK/Erk or activation of PI3K/Akt, which may be acquired by directly affecting genes in each pathway, by upregulation of receptor tyrosine kinases, or by affecting downstream signaling. BRAF inhibitor resistance increases invasiveness through changes in phosphorylation actin cytoskeleton regulators and increased extracellular matrix metalloprotease expression. Resistant cells have also been shown to undergo metabolic reprogramming characterized by increased glutamine or serine dependence. A375 cells have been used to model BRAF inhibitor resistance across multiple studies, but the methods and conclusions vary. To improve preclinical in vitro research, future studies of BRAF inhibitor resistance in melanoma should include multiple cell lines, consider a continuous-dose tre...
Source: Frontiers in Oncology - Category: Cancer & Oncology Source Type: research