mk-2206 and Carcinoma--Papillary

The BRAF V600E mutation is commonly observed in papillary thyroid cancer (PTC) and predominantly activates the MAPK pathway. Presence of BRAF V600E predicts increasing risk of recurrence and higher mortality rate, and treatment options for such patients are limited. Vemurafenib, a BRAF V600E inhibitor, is initially effective, but cells inevitably develop alternative mechanisms of pathway activation. Mechanisms of primary resistance have been described in short-term cultures of PTC cells; however, mechanisms of acquired resistance have not. In the present study, we investigated possible adaptive mechanisms of BRAF V600E inhibitor resistance in KTC1 thyroid cancer cells following long-term vemurafenib exposure. We found that a subpopulation of KTC1 cells acquired resistance to vemurafenib following 5 months of treatment with the inhibitor. Resistance coincided with the spontaneous acquisition of a KRAS G12D activating mutation. Increases in activated AKT, ERK1/2, and EGFR were observed in these cells. In addition, the resistant cells were less sensitive to combinations of vemurafenib and MEK1 inhibitor or AKT inhibitor. These results support the KRAS G12D mutation as a genetic mechanism of spontaneously acquired secondary BRAF inhibitor resistance in BRAF V600E thyroid cancer cells.

Topics: Aged; Antineoplastic Agents; Benzimidazoles; Carcinoma, Papillary; Cell Line, Tumor; Drug Resistance, Neoplasm; Enzyme Inhibitors; ErbB Receptors; Female; Gain of Function Mutation; Gene Knockdown Techniques; Heterocyclic Compounds, 3-Ring; Humans; Indoles; Male; MAP Kinase Kinase 1; MAP Kinase Signaling System; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Proto-Oncogene Proteins B-raf; Proto-Oncogene Proteins c-akt; Proto-Oncogene Proteins p21(ras); Pyridones; Pyrimidines; RNA Interference; RNA, Small Interfering; Sulfonamides; Thyroid Cancer, Papillary; Thyroid Neoplasms; Vemurafenib

A major challenge in tumor therapy is the decrease or even the halting of cell proliferation and migration of cancerous cells. In the present study, we have analyzed the impact of a pharmacological blockade of the PI3K/Akt and MAPK/ERK1/2 signaling pathways on cell migration, proliferation and cell death in three human thyroid tumor cell lines that represent the main types of malignant thyroid carcinomas (B-CPAP, follicular; Cal-62, anaplastic; FTC-133, papillary thyroid carcinoma cells) and in which these pathways are constitutively activated. In general, pharmacological perturbation of PI3/Akt (application of MK-2206) and MEK/ERK1/2 (application of PD0325901 or U0126) signaling led to a cell line and drug-specific decrease in the proliferation and migration potential of thyroid carcinoma cells, although to a varying extent. However, one exception became apparent: in Cal-62 cells inhibition of the MEK/ERK1/2 module increased the migration rate up to 50%. This effect could be prevented by a simultaneous suppression of the PI3/Akt pathway, but also by application of the multiple kinase inhibitor sorafenib, a treatment that did not change the activation state of Akt. Thus, a pharmacological perturbation of canonical signaling pathways in thyroid carcinoma may induce drug-dependent yin-yang effects that are characterized by a simultaneous suppression of one (i.e., proliferation) and the activation of another (i.e., migration) cellular process. The appearance of such phenomena should be taken into account when therapy plans are established.

Topics: Benzamides; Carcinoma; Carcinoma, Papillary; Cell Line, Tumor; Cell Movement; Cell Proliferation; Diphenylamine; Gene Expression Regulation, Neoplastic; Heterocyclic Compounds, 3-Ring; Humans; MAP Kinase Signaling System; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Signal Transduction; Thyroid Cancer, Papillary; Thyroid Neoplasms; Yin-Yang