KRAS G12V Mutation in Acquired Resistance to Combined BRAF and MEK Inhibition in Papillary Thyroid Cancer
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Medical University of South Carolina, Charleston, South Carolina.
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BRAF V600E mutations occur in approximately 40% of all patients with papillary thyroid cancer (PTC) and are associated with a worse prognosis in population studies. Treatment with single-agent BRAF inhibitors can result in nondurable partial responses (PRs) in clinical trials, but resistance inevitably develops. The mechanisms of resistance are not completely understood, but in non-thyroid tumors harboring BRAF V600E mutations, resistance has been ascribed to concurrent or acquired mutations in MEK1/2, RAC1, KRAS, and NRAS. This case report describes a patient with radioactive iodine–refractory metastatic PTC treated in a clinical trial with combination BRAF and MEK inhibition who achieved a durable PR. At time of progression, biopsy revealed an acquired KRAS G12V–activating mutation. The patient subsequently went on to have a PR to cabozantinib therapy in the clinical trial. This is the first reported case of an acquired KRAS-activating mutation that developed during treatment with BRAF and MEK inhibition in a patient with BRAF-mutated PTC. The KRAS mutation was also detected in peripheral blood samples taken as part of the trial, indicating that resistant mutations may be identified through noninvasive means. The identification of resistant mutations in patients at time of progression is necessary to identify possible therapeutic options including potential clinical trials.
ClinicalTrials.gov identifier: NCT01723202
Submitted August 29, 2018; accepted for publication March 4, 2019.
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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