An approach to suppress the evolution of resistance in BRAFV600E-mutant cancer

摘要: The principles that govern the evolution of tumors exposed to targeted therapy are poorly understood. Here we modeled selection and propagation an amplification in BRAF oncogene (BRAFamp) patient-derived tumor xenografts (PDXs) were treated with a direct inhibitor kinase ERK, either alone or combination other ERK signaling inhibitors. Single-cell sequencing multiplex fluorescence situ hybridization analyses mapped emergence extra-chromosomal parallel evolutionary trajectories arose same shortly after treatment. BRAFamp was determined by fitness threshold, barrier subclonal populations need overcome regain presence therapy. This differed for inhibitors signaling, suggesting sequential monotherapy is ineffective selects progressively higher copy number. Concurrent targeting RAF, MEK kinases, however, imposed sufficiently high threshold prevent subclones high-level BRAFamp. When administered on intermittent schedule, this treatment inhibited growth 11/11 PDXs lung cancer melanoma without apparent toxicity mice. Thus, gene can be acquired expanded through evolution, enabling adapt while maintaining their intratumoral heterogeneity. Treatments impose highest will likely resistance-causing alterations and, thus, merit testing patients.