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 mutations are the most common cause for this activation in PTC, occurring in 25% to 49% of tumors. trial. This is the first reported case of an acquired 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: 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)Crefractory, 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 Dantrolene sodium RAS/RAF/MEK/ERK pathway, a key oncogenic signaling cascade for many human malignancies.3 Activating 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.4C6 Although there Dantrolene sodium 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, 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 V600E mutant alleles.10C13 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 V600ECmutated thyroid cancer cell line selected for resistance to vemurafenib developed an acquired novel G12DCactivating mutation. Cabanillas et al15 reported a case of a patient with anaplastic thyroid carcinoma treated with dabrafenib/trametinib in whom an Q61K mutation was discovered on tumor tissue after 4 weeks of treatment. The present case report describes for Dantrolene sodium the first time the development of an activating G12V Dantrolene sodium mutation as a potential resistance mechanism in a patient with PTC treated with combination dabrafenib/trametinib who experienced a subsequent response to cabozantinib. Case Report A 67-year-old woman diagnosed with PTC underwent total thyroidectomy with central neck dissection, which revealed a 7.2-cm extensive right lobar, poorly differentiated PTC with 3 of 9 lymph nodes positive and a background of Hashimoto thyroiditis. Following surgical resection, imaging revealed bilateral pulmonary nodules and mediastinal adenopathy. She received 100.9 mCi of RAI therapy, and a posttreatment scan showed uptake in the thyroid bed but none in the chest. The tumor was staged as a pT3pN1aM0 poorly DTC. Repeat imaging 6 months after initial diagnosis and treatment revealed increasing adenopathy in the neck and bilateral subcentimeter pulmonary nodules, and the patient underwent right radical neck dissection with 4 of 52 examined lymph nodes positive for PTC, with no extranodal extension noted. Six months later, imaging again revealed an enlarged right paratracheal node and anterior paratracheal node, which were resected Mouse monoclonal to CD29.4As216 reacts with 130 kDa integrin b1, which has a broad tissue distribution. It is expressed on lympnocytes, monocytes and weakly on granulovytes, but not on erythrocytes. On T cells, CD29 is more highly expressed on memory cells than naive cells. Integrin chain b asociated with integrin a subunits 1-6 ( CD49a-f) to form CD49/CD29 heterodimers that are involved in cell-cell and cell-matrix adhesion.It has been reported that CD29 is a critical molecule for embryogenesis and development. It also essential to the differentiation of hematopoietic stem cells and associated with tumor progression and metastasis.This clone is cross reactive with non-human primate and determined to be positive for PTC. The patient went on to receive external-beam radiotherapy to the neck at an outside institution. She was then started on sorafenib, 400 mg twice daily, which initially was poorly tolerated and she developed hand-foot syndrome and diarrhea. With the aid of supportive measures and minimal dose interruption, she was able to remain on sorafenib at 400 mg twice daily for 2 years with stable disease as the best response (supplemental eFigure 1, available with this article at JNCCN.org). After experiencing progressive disease, the patient was enrolled in a clinical trial and started on lenvatinib (ClinicalTrials.gov identifier: ).1 She remained on lenvatinib, 24 mg daily, for 6 months before experiencing progressive disease in both the neck and chest. Her treatment course was complicated.