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.
Author contributions: Study concept and design: Owen, Konda, Sipos, Ringel, Timmers, Shah. Data acquisition: Owen, Konda, Sipos, Liu, Ringel, Timmers, Shah. Data analysis and interpretation: All authors. Drafting of manuscript: Owen, Konda, Ringel, Timmers, Shah. Critical revision: All authors. Final approval: All authors.
Disclosures: Dr. Shah has disclosed that she is a scientific advisor for Novartis and receives grant/research support from Eisai Inc. The remaining authors have not received any financial consideration from any person or organization to support the preparation, analysis, results, or discussion of this article.
Funding: Clinical study NCT01723202 was approved and funded in part by the NCCN Oncology Research Program (NCCNGSK20008). Support for this research was provided by The Ohio State University Comprehensive Cancer Center using Pelotonia funds.
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