Figure 1.

Model of thyroid carcinoma clonal evolution. PTC-derived KTC1 cells clonally harbor the hallmark heterozygous BRAF^WT/V600E mutation and show loss of the CDKN2A (P16) gene. The diploid clones compose the majority of the tumor cells genetic landscape; with there being other subclonal populations present within the overall tumor. Upon treatment with targeted therapy, in this case using the selective BRAF^V600E inhibitor, vemurafenib, diploid KTC1 clones will respond positively to the drug treatment and die. However, those clones containing additional subclonal mutations, such as mutations in RBMX and RBM10 genes, or chromosome 5p amplifications, are able to overcome drug induced suppression of the BRAF^V600E pathway. Through the course of vemurafenib treatment, subclones with passenger mutations, such as RBM gene family somatic mutations, can be positively selected. This tumor geography will then become enriched with populations of drug resistant mutant clones. This tumor composed primarily of vemurafenib-resistant clones, might be effectively untreatable and has the potential to lead to tumor progression.