| Authors |
Marlow L.A., Rohl S.D., Kennedy G.T., Milosevic D., Grebe S.K., Reddi H.V., Eberhardt N.L., Morris J.C., Trujillo M.A., McDonough S.J., McIver B., Bible K.C., Casler J., Smallridge R.C., Copland J.A. |
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| Abstract |
Follicular thyroid carcinoma (FTC) is a well-differentiated cancer that
encompasses 15-20% of all thyroid cancers and invasion is frequently seen
in the vascular structures within the thyroid gland and neck. FTC is
associated with up to 40% of all thyroid cancer related deaths with no
curative treatments beyond surgery and 131 Iodine. We report three new
authenticated FTC cell lines (SDAR1, SDAR2, SDAR3) from a patient
diagnosed with metastatic FTC to a lymph node and neck mass. A fourth FTC
cell line (THJ-306T) was derived from another FTC patient, all of which
had features of radioiodide insensitive tumors. Short tandem DNA repeat
(STR) analysis validated that the cell lines were derived from the patient
tumor tissues. Interestingly, the SDAR cell lines were not mutated for
retinoblastoma (Rb), KRas, HRas, PI3K, BRAFV600E or PAX8/PPARgamma.
However, the primary tumor cell line, SDAR1, was mutant for p53.
Expression of Pax8 and TSHR mRNA were present while PDS, DIO2, TPO and NIS
were absent. For the 4th FTC cell line, THJ-306T, contained Rb and NRas
codon 61 mutations and expressed TTF1 and Pax8 mRNA. With respect to
oncogenic signaling pathways, pERK and pAkt were elevated in all four cell
lines. Based upon these findings we tested and demonstrated antitumor
proliferative synergy using a MEK inhibitor (GSK-1120212) combined with an
Akt inhibitor (MK-2206). Using IC50 concentrations and fixed ratio drug
concentrations, CI values for combinatorial therapy were 0.071, 0.29, 0.24
and 0.29 respectively for SDAR1, SDAR2, SDAR3 and THJ-306T. Propidium
iodide measurement of cell death revealed synergy of the combinatorial
therapy. Thus, inhibiting these two oncogenic pathways in four new FTC
cell lines demonstrated strong antitumor synergy. We are currently
examining the role of RhoB which may play a role in the observed synergy.
Moreover, with the recent discovery that inhibition of the Akt pathway
leads to NIS re-expression and radioiodide uptake, we are exploring
whether these cells when exposed to combinatorial therapy respond to
iodine uptake and retention.
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