| Summary: | <i>BRAF</i>-activating mutations are the most frequent driver mutations in papillary thyroid cancer (PTC). Targeted inhibitors such as dabrafenib have been used in advanced <i>BRAF</i>-mutated PTC; however, acquired resistance to the drug is common and little is known about other effectors that may play integral roles in this resistance. In addition, the induction of PTC dedifferentiation into highly aggressive <i>KRAS</i>-driven anaplastic thyroid cancer (ATC) has been reported. We detected a novel <i>RAC1</i> (P34R) mutation acquired during dabrafenib treatment in a progressive metastatic lesion with ATC phenotype. To identify a potential functional link between this novel mutation and tumor dedifferentiation, we developed a cell line derived from the metastatic lesion and compared its behavior to isogenic cell lines and primary tumor samples. Our data demonstrated that <i>RAC1</i> mutations induce changes in cell morphology, reorganization of F-actin almost exclusively at the cell cortex, and changes in cell adhesion properties. We also established that <i>RAC1</i> amplification, with or without mutation, is sufficient to drive cell proliferation and resistance to <i>BRAF</i> inhibition. Further, we identified polyploidy of chromosome 7, which harbors <i>RAC1</i>, in both the metastatic lesion and its derived cell line. Copy number amplification and overexpression of other genes located on this chromosome, such as <i>TWIST1</i>, <i>EGFR</i>, and <i>MET</i> were also detected, which might also lead to dabrafenib resistance. Our study suggests that polyploidy leading to increased expression of specific genes, particularly those located on chromosome 7, should be considered when analyzing aggressive thyroid tumor samples and in further treatments.
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