Tyrosine kinase inhibitor therapy and metabolic remodelling in papillary thyroid cancer

Abstract

<jats:p>The present study used [18F]FDG-PET to study glucose metabolism and tumor responses for thyroid cancer xenografts expressing the glycolytic pathway modulators platelet-derived growth factor receptor (PDGFR) and BRAFV600E. PET data were correlated with immunohistochemistry staining and kinetic analysis for facilitative glucose transporter 1 (GLUT1) and hexokinase-II (HK2). Vemurafenib decreased [18F]FDG uptake in BCPAP cells in vitro; however, it was increased by ~70% with imatinib application to BCPAP cells. This metabolic response to tyrosine kinase inhibition required BRAFV600E as it was not observed in cell lines lacking mutated BRAF (TPC1). In xenografts, imatinib therapy in BCPAP thyroid tumour-bearing mice significantly increased [18F]FDG uptake and retention (&gt;30%) in BCPAP tumours with PDGFRβ or both (α+β) isoforms. Kinetic analysis revealed that the increased glucose uptake is a consequence of increased phosphorylation and intracellular trapping of [18F]FDG confirmed by an increase in HK2 protein expression and activity, but not GLUT1 activity. BRAF inhibition alone, or combined PDGFR and BRAF inhibition, reduced (~60%) [18F]FDG uptake in both types of BCPAP (β or α+β) tumours. Combination therapy with imatinib and vemurafenib led to a near abolition of the tumors (~90% reduction). Still, single treatment for BCPAP with PDGFRα expression was much less effective. In summary, imatinib led to a paradoxical increase of [18F]FDG uptake in xenografts that was reversed through BRAFV600E inhibition. Our data show that metabolic reprogramming in thyroid cancer occurs as a consequence of BRAF-mediated upregulation of HK2 expression that may permit tumour growth with isolated blockade of upstream tyrosine kinase receptors.</jats:p>

SGLT2 inhibition restrains thyroid cancer growth via G1/S phase transition arrest and apoptosis mediated by DNA damage response signaling pathways

“…High rate of glycolysis is mainly related to increased cellular glucose uptake in cancer cells. More and more evidence showed that abnormal glucose metabolism is closely related to the occurrence and development of thyroid cancer [ 7 , 8 ]. Moreover, thyroid cancer cells with higher malignancy also featured with stronger glycolytic activity [ 9 ].…”

Reprogramming of Cellular Metabolism and Its Therapeutic Applications in Thyroid Cancer

“…The in vitro experiments also revealed that thyroid cancer cells with BRAF V600E (BCPAP and 8505C cells) are more glycolytic than those without via HIF1α-MYC-peroxisome proliferator-activated receptor γ coactivator 1β (PGC1β) axis [29,57], and that glucose uptake is suppressed by vemurafenib, a BRAF inhibitor, in BCPAP cells having BRAF V600E [29,54]. Of interest, Lee et al have found localization of BRAF V600E not only in the cytoplasm but also in mitochondria in PCCl3-BRAF V600E cells.…”

“…In the in vitro experimental settings, growth of eight human thyroid cancer cell lines, including 8505C, K18, C643, TPC1, etc., is largely dependent on glucose [51]. Compared to Nthy-ori 3-1 cells, an immortalized normal human thyroid cell line, BCPAP and TPC1 cells are more glycolytic, as demonstrated by higher glucose uptake, LDH production and expression levels of GLUT1 and HK1/2, although their mitochondrial function is intact [31,[52][53][54]. LDHA knockdown (KD) and overexpression decreases and increases the migration and invasion of these cells, respectively.…”

Metabolic Reprogramming of Thyroid Cancer Cells and Crosstalk in Their Microenvironment

“…However, glucose uptake and metabolism in thyroid tumor cells were downregulated when BRAF V600E was blocked by vemurafenib. In terms of tumor growth, combination therapy of imatinib and vemurafenib was much more effective than single therapy and led to a near abolition of the tumors ( 158 ). The combination of imatinib and HK2 inhibitors may solve the problem of drug resistance and also provide better efficacy in TC.…”