Abstract

<div>AbstractPurpose:<p>Activating BRAF mutations, most commonly BRAF<sup>V600E</sup>, are a major oncogenic driver of many cancers. We explored whether BRAF<sup>V600E</sup> promotes radiation resistance and whether selectively targeting BRAF<sup>V600E</sup> with a BRAF inhibitor (vemurafenib, BRAFi) sensitizes BRAF<sup>V600E</sup> thyroid cancer cells to radiotherapy.</p>Experimental Design:<p>Immunoblotting, neutral comet, immunocytochemistry, functional reporter, and clonogenic assays were used to analyze the outcome and molecular characteristics following radiotherapy with or without BRAF<sup>V600E</sup> or vemurafenib in thyroid cancer cells.</p>Results:<p>BRAF<sup>V600E</sup> thyroid cancer cell lines were associated with resistance to ionizing radiation (IR), and expression of BRAF<sup>V600E</sup> into wild-type BRAF thyroid cancer cells led to IR resistance. BRAFi inhibited ERK signaling in BRAF<sup>V600E</sup> mutants, but not BRAF wild-type thyroid cancer cell lines. BRAFi selectively radiosensitized and delayed resolution of IR-induced γH2AX nuclear foci in BRAF<sup>V600E</sup> cells. Moreover, BRAFi impaired global DNA repair and altered the resolution of 53BP1 and RAD51 nuclear foci in BRAF<sup>V600E</sup> cells following IR. BRAF<sup>V600E</sup> mutants displayed enhanced nonhomologous end-joining (NHEJ) repair activity, which was abolished by BRAFi. Intriguingly, BRAF<sup>V600E</sup> mutation led to upregulation of XLF, a component of NHEJ, which was prevented by BRAFi. Importantly, BRAFi in combination with radiotherapy resulted in marked and sustained tumor regression of BRAF<sup>V600E</sup> thyroid tumor xenografts.</p>Conclusions:<p>BRAF<sup>V600E</sup> mutation promotes NHEJ activity leading to radioresistance and BRAFi selectively radiosensitizes BRAF<sup>V600E</sup> thyroid cancer cells through inhibiting NHEJ. Our findings suggest that combining BRAFi and radiation may improve the therapeutic outcome of patients with BRAF<sup>V600E</sup>-mutant thyroid cancer.</p></div>

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