Rac1 alterations induce acquired dabrafenib resistance in association with anaplastic transformation in a papillary thyroid cancer patient

• Type of Material: Article
• Authors: Rozita Bagheri-Yarmand, University of Texas MD Anderson Cancer Center; Naifa L Busaidy, University of Texas MD Anderson Cancer Center; Elena McBeath, University of Texas MD Anderson Cancer Center; Brian P Danysh, University of Texas MD Anderson Cancer Center; Kurt W Evans, University of Texas MD Anderson Cancer Center; Tyler J Moss, University of Texas MD Anderson Cancer Center; Argun Akcakanat, University of Texas MD Anderson Cancer Center; Patrick KS Ng, University of Texas MD Anderson Cancer Center; Christina M Knippler, Emory University; Jalyn A Golden, University of Texas MD Anderson Cancer Center; Michelle D Williams, University of Texas MD Anderson Cancer Center; Asha S Multani, University of Texas MD Anderson Cancer Center; Maria E Cabanillas, University of Texas MD Anderson Cancer Center; Kenna R Shaw, University of Texas MD Anderson Cancer Center; Funda Meric-Bernstam, University of Texas MD Anderson Cancer Center; Manisha H Shah, The Ohio State University Wexner Medical Center; Matthew D Ringel, The Ohio State University Wexner Medical Center; Marie Claude Hofmann, University of Texas MD Anderson Cancer Center
• Language: English
• Date: 2021-10-01
• Publisher: Emory University Libraries
• Publication Version: Final Published Version
• Copyright Statement: © 2021 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.3390/cancers13194950
• Title of Journal or Parent Work: Cancers
• Volume: 13
• Issue: 19
• Grant/Funding Information: This work was funded by grants NIH P50 CA168505 (M.D.R.), NIH R01 CA227847 (M.D.R., (M.-C.H)), MD Anderson Cancer Center Support grant (NIH P30 CA016672), MD Anderson SPORE Bridge Funding ((M.-C.H)), Novartis (N.L.B.), American Thyroid Association fellowship (B.P.D.), U54CA224065 (F.M.-B.), CTSA-Informatics Core NIH 1UL1TR003167, Sheikh Khalifa Bin Zayed Al Nahyan Institute for Personalized Cancer Therapy, Clinical Trial NCT01723202 (M.H.S.), and Clinical trial NCT01772771 (F.M.-B.).
• Keywords: BRAF; aneuploidy; kinase inhibitors; anaplastic thyroid carcinoma; PAK1; papillary thyroid carcinoma; drug resistance; RAC1
• Research Categories: Health Sciences, Oncology

Abstract

BRAF-activating mutations are the most frequent driver mutations in papillary thyroid cancer (PTC). Targeted inhibitors such as dabrafenib have been used in advanced BRAF-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 KRAS-driven anaplastic thyroid cancer (ATC) has been reported. We detected a novel RAC1 (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 RAC1 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 RAC1 amplification, with or without mutation, is sufficient to drive cell proliferation and resistance to BRAF inhibition. Further, we identified polyploidy of chromosome 7, which harbors RAC1, in both the metastatic lesion and its derived cell line. Copy number amplification and overexpression of other genes located on this chromosome, such as TWIST1, EGFR, and MET 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.