Over the past several years, clinical trials have led to FDA approval of the multikinase inhibitors (MKI) lenvatinib (February 2015)1 and sorafenib (November 2013)2 for treatment of radioactive iodine (RAI)–refractory, progressive, differentiated thyroid cancer (DTC). Yet, for both of these MKIs, acquired resistance is universal, adverse events are common, and no overall survival benefit has been demonstrated. Papillary thyroid cancer (PTC) is primarily driven by constitutive activation of the RAS/RAF/MEK/ERK pathway, a key oncogenic signaling cascade for many human malignancies.3 Activating BRAF mutations are the most common cause for this activation in PTC, occurring in 25% to 49% of tumors. Moreover, the presence of this mutation is associated with more advanced disease and poorer prognosis.4–6 Although there are currently no approved BRAF-targeted treatments for patients with PTC, a phase II trial of the BRAF inhibitor vemurafenib in patients with RAI-refractory, BRAF-mutated PTC demonstrated a response rate of 35%.7 Resistance to BRAF inhibition is likely to develop eventually, which has been demonstrated in melanoma, and is thought to occur through reactivation of the MAPK pathway.8
Combination dabrafenib/trametinib is now the standard therapy for patients with melanoma harboring BRAF V600E mutations based on increased response rates and overall survival.9 However, resistance to dual inhibition eventually develops in most patients due to somatic mutations in MEK1/2, KRAS, or NRAS, and amplification of the BRAF V600E mutant alleles.10–13 Mechanisms of resistance to combination BRAF and MEK inhibition remain to be fully elucidated in PTC. Danysh et al14 reported in vitro studies wherein a BRAF V600E–mutated thyroid cancer cell line selected for resistance to vemurafenib developed an acquired novel KRAS G12D–activating mutation. Cabanillas et al15 reported a case of a patient with anaplastic thyroid carcinoma treated with dabrafenib/trametinib in whom an NRAS Q61K mutation was discovered on tumor tissue after 4 weeks of treatment. The present case report describes for the first time the development of an activating KRAS G12V mutation as a potential resistance mechanism in a patient with PTC treated with combination dabrafenib/trametinib who experienced a subsequent response to cabozantinib.
Clinical study NCT01723202 was approved and funded in part by the NCCN Oncology Research Program, with general research support provided by Novartis. NCT01811212 was sponsored by the NCI Cancer Therapy Evaluation Program and the International Thyroid Oncology Group (ITOG). NCT01321554 was sponsored by Eisai Inc.
Schlumberger MTahara MWirth LJ. Lenvatinib versus placebo in radioiodine-refractory thyroid cancer. N Engl J Med 2015;372:621–630.
Brose MSNutting CMJarzab B. Sorafenib in radioactive iodine-refractory, locally advanced or metastatic differentiated thyroid cancer: a randomised, double-blind, phase 3 trial. Lancet 2014;384:319–328.
McCubrey JASteelman LSChappell WH. Roles of the Raf/MEK/ERK pathway in cell growth, malignant transformation and drug resistance. Biochim Biophys Acta 2007;1773:1263–1284.
Brzezianska EPastuszak-Lewandoska D. A minireview: the role of MAPK/ERK and PI3K/Akt pathways in thyroid follicular cell-derived neoplasm. Front Biosci 2011;16:422–439.
Xing MWestra WHTufano RP. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab 2005;90:6373–6379.
Brose MSCabanillas MECohen EE. Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. Lancet Oncol 2016;17:1272–1282.
- Search Google Scholar
- Export Citation
)| false . , Brose MS , Cabanillas ME , Cohen EE Vemurafenib in patients with BRAF(V600E)-positive metastatic or unresectable papillary thyroid cancer refractory to radioactive iodine: a non-randomised, multicentre, open-label, phase 2 trial. 2016; 17: 1272– 1282. 10.1016/S1470-2045(16)30166-8 27460442
Rizos HMenzies AMPupo GM. BRAF inhibitor resistance mechanisms in metastatic melanoma: spectrum and clinical impact. Clin Cancer Res 2014;20:1965–1977.
Long GVStroyakovskiy DGogas H. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med 2014;371:1877–1888.
Ahronian LGSennott EMVan Allen EM. Clinical acquired resistance to RAF inhibitor combinations in BRAF-mutant colorectal cancer through MAPK pathway alterations. Cancer Discov 2015;5:358–367.
Gowrishankar KSnoyman SPupo GM. Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition. J Invest Dermatol 2012;132:1850–1859.
Wagle NVan Allen EMTreacy DJ. MAP kinase pathway alterations in BRAF-mutant melanoma patients with acquired resistance to combined RAF/MEK inhibition. Cancer Discov 2014;4:61–68.
Corcoran RBAndré TAtreya CE. Combined BRAF, EGFR, and MEK inhibition in patients with BRAF V600E-mutant colorectal cancer. Cancer Discov 2018;8:428–443.
Danysh BPRieger EYSinha DK. Long-term vemurafenib treatment drives inhibitor resistance through a spontaneous KRAS G12D mutation in a BRAF V600E papillary thyroid carcinoma model. Oncotarget 2016;7:30907–30923.
Cabanillas MEFerrarotto RGarden AS. Neoadjuvant BRAF- and immune-directed therapy for anaplastic thyroid carcinoma. Thyroid 2018;28:945–951.
Cabanillas MEHu MIDurand JB. Challenges associated with tyrosine kinase inhibitor therapy for metastatic thyroid cancer. J Thyroid Res 2011;2011:985780.
Kloos RTRingel MDKnopp MV. Phase II trial of sorafenib in metastatic thyroid cancer. J Clin Oncol 2009;27:1675–1684.
Flaherty KTInfante JRDaud A. Combined BRAF and MEK inhibition in melanoma with BRAF V600 mutations. N Engl J Med 2012;367:1694–1703.
Rothenberg SMMcFadden DGPalmer EL. Redifferentiation of iodine-refractory BRAF V600E-mutant metastatic papillary thyroid cancer with dabrafenib. Clin Cancer Res 2015;21:1028–1035.
Cheng LJin YLiu M. HER inhibitor promotes BRAF/MEK inhibitor-induced redifferentiation in papillary thyroid cancer harboring BRAFV600E. Oncotarget 2017;8:19843–19854.
Ho ALGrewal RKLeboeuf R. Selumetinib-enhanced radioiodine uptake in advanced thyroid cancer. N Engl J Med 2013;368:623–632.
Dunn LASherman EJBaxi SS. Vemurafenib redifferentiation of BRAF mutant RAI-refractory thyroid cancers. J Clin Endocrinol Metab 2019;104:1417–1428.
Baitei EYZou MAl-Mohanna F. Aberrant BRAF splicing as an alternative mechanism for oncogenic B-Raf activation in thyroid carcinoma. J Pathol 2009;217:707–715.
Byeon HKNa HJYang YJ. c-Met-mediated reactivation of PI3K/AKT signaling contributes to insensitivity of BRAF(V600E) mutant thyroid cancer to BRAF inhibition. Mol Carcinog 2016;55:1678–1687.
Duquette MSadow PMHusain A. Metastasis-associated MCL1 and P16 copy number alterations dictate resistance to vemurafenib in a BRAF V600E patient-derived papillary thyroid carcinoma preclinical model. Oncotarget 2015;6:42445–42467.
- Search Google Scholar
- Export Citation
)| false . , Duquette M , Sadow PM , Husain A Metastasis-associated. MCL1and P16 copy number alterations dictate resistance to vemurafenib in a BRAFV600E patient-derived papillary thyroid carcinoma preclinical model 2015; 6: 42445– 42467. 10.18632/oncotarget.6442
Falchook GSMillward MHong D. BRAF inhibitor dabrafenib in patients with metastatic BRAF-mutant thyroid cancer. Thyroid 2015;25:71–77.
Konda BShah MHWei L. Evaluation of BRAFV600E levels in cell-free DNA (CFDNA) as a biomarker of response in BRAF V600E mutated radioactive iodine refractory (RAIR) differentiated thyroid cancer (DTC) treated with dabrafenib alone or in combination with trametinib. Presented at the 87th Annual Meeting of the American Thyroid Association; October 18–22 2017; Victoria British Columbia Canada.
Oddo DSennott EMBarault L. Molecular landscape of acquired resistance to targeted therapy combinations in BRAF-mutant colorectal cancer. Cancer Res 2016;76:4504–4515.
Johnson DBMenzies AMZimmer L. Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. Eur J Cancer 2015;51:2792–2799.
- Search Google Scholar
- Export Citation
)| false . , Johnson DB , Menzies AM , Zimmer L Acquired BRAF inhibitor resistance: a multicenter meta-analysis of the spectrum and frequencies, clinical behaviour, and phenotypic associations of resistance mechanisms. 2015; 51: 2792– 2799. 10.1016/j.ejca.2015.08.022 26608120
Hatzivassiliou GLiu BO’Brien C. ERK inhibition overcomes acquired resistance to MEK inhibitors. Mol Cancer Ther 2012;11:1143–1154.
Sherman SIClary DOElisei R. Correlative analyses of RET and RAS mutations in a phase 3 trial of cabozantinib in patients with progressive, metastatic medullary thyroid cancer. Cancer 2016;122:3856–3864.
Fujita-Sato SGaleas JTruitt M. Enhanced MET translation and signaling sustains K-Ras-driven proliferation under anchorage-independent growth conditions. Cancer Res 2015;75:2851–2862.
Iyer PCDadu RGule-Monroe M. Salvage pembrolizumab added to kinase inhibitor therapy for the treatment of anaplastic thyroid carcinoma. J Immunother Cancer 2018;6:68.