An approach to suppress the evolution of resistance in BRAF^V600E-mutant cancer.

ABSTRACT: The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled the selection and propagation of an amplification in the BRAF oncogene (BRAF^amp) in patient-derived tumor xenografts (PDXs) that were treated with a direct inhibitor of the kinase ERK, either alone or in combination with other ERK signaling inhibitors. Single-cell sequencing and multiplex fluorescence in situ hybridization analyses mapped the emergence of extra-chromosomal amplification in parallel evolutionary trajectories that arose in the same tumor shortly after treatment. The evolutionary selection of BRAF^amp was determined by the fitness threshold, the barrier that subclonal populations need to overcome to regain fitness in the presence of therap

SUBMITTER: Xue Y 

PROVIDER: S-EPMC5696266 | biostudies-literature | 2017 Aug

REPOSITORIES: biostudies-literature