crizotinib and Thyroid-Carcinoma--Anaplastic

Anaplastic thyroid carcinomas (ATCs) have a high prevalence of BRAF and TP53 mutations. A trial of vemurafenib in nonmelanoma BRAFV600E-mutant cancers showed significant, although short-lived, responses in ATCs, indicating that these virulent tumors remain addicted to BRAF despite their high mutation burden. To explore the mechanisms mediating acquired resistance to BRAF blockade, we generated mice with thyroid-specific deletion of p53 and dox-dependent expression of BRAFV600E, 50% of which developed ATCs after dox treatment. Upon dox withdrawal there was complete regression in all mice, although recurrences were later detected in 85% of animals. The relapsed tumors had elevated MAPK transcriptional output, and retained responses to the MEK/RAF inhibitor CH5126766 in vivo and in vitro. Whole-exome sequencing identified recurrent focal amplifications of chromosome 6, with a minimal region of overlap that included Met. Met-amplified recurrences overexpressed the receptor as well as its ligand Hgf. Growth, signaling, and viability of Met-amplified tumor cells were suppressed in vitro and in vivo by the Met kinase inhibitors PF-04217903 and crizotinib, whereas primary ATCs and Met-diploid relapses were resistant. Hence, recurrences are the rule after BRAF suppression in murine ATCs, most commonly due to activation of HGF/MET signaling, which generates exquisite dependency to MET kinase inhibitors.

Topics: Amino Acid Substitution; Animals; Antineoplastic Agents; Cell Line, Tumor; Coumarins; Crizotinib; Disease Models, Animal; Drug Resistance, Neoplasm; Genes, p53; Humans; Indoles; MAP Kinase Signaling System; Mice; Mice, Transgenic; Mutation, Missense; Protein Kinase Inhibitors; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-met; Pyrazines; Sulfonamides; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Triazoles

Topics: Aged; Anaplastic Lymphoma Kinase; Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Chemotherapy, Adjuvant; Crizotinib; Female; Gene Rearrangement; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Neoplasm Staging; Precision Medicine; Predictive Value of Tests; Protein Kinase Inhibitors; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Remission Induction; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms; Thyroidectomy; Time Factors; Tomography, X-Ray Computed; Treatment Outcome

Thyroid carcinoma is the most common endocrine malignant tumor and accounts for 1% of all new malignant diseases. Among all types and subtypes of thyroid cancers that have been described so far, papillary thyroid carcinoma is the most frequent. The standard management treatment of these tumors consists of surgery, followed by radioiodine treatment in case of high risk of relapse. The most aggressive forms are commonly treated by chemotherapy, radiotherapy or experimental drug testing. We recently reported the case of a patient presenting an anaplastic thyroid carcinoma with lung metastases. Fluorescence in situ hybridization analysis allowed us to detect a rearrangement of the anaplastic lymphoma kinase (ALK) gene in both tumors. The patient was treated with crizotinib and presented an excellent drug response. We present here the subsequent investigations carried out to further characterize this genetic alteration and to assess the prevalence of ALK rearrangements in thyroid lesions. High resolution array-comparative genomic hybridization data complemented by RT-PCR and sequencing analyses, allowed us to demonstrate the presence of a STRN/ALK fusion. The STRN/ALK transcript consisted of the fusion between exon 3 of STRN and exon 20 of ALK. Subsequent screening of 75 various thyroid tumors by RT-PCR revealed that 2 out of 29 papillary thyroid carcinomas exhibited the same fusion transcript. None was detected in other types of malignant or benign thyroid lesions analyzed. These findings could pave the way for the development of new targeted therapeutic strategies in the treatment of papillary thyroid carcinomas and point to ALK inhibitors as promising agents that merit rapid evaluation.

Topics: Anaplastic Lymphoma Kinase; Base Sequence; Calmodulin-Binding Proteins; Comparative Genomic Hybridization; Crizotinib; Gene Fusion; Gene Rearrangement; Humans; Immunohistochemistry; In Situ Hybridization, Fluorescence; Lung Neoplasms; Membrane Proteins; Molecular Sequence Data; Nerve Tissue Proteins; Pyrazoles; Pyridines; Receptor Protein-Tyrosine Kinases; Reverse Transcriptase Polymerase Chain Reaction; Sequence Analysis, DNA; Thyroid Carcinoma, Anaplastic; Thyroid Neoplasms