Persistent RET activation is a frequent event in
papillary thyroid carcinoma (PTC) and medullary
thyroid carcinoma (MTC). In these
cancers, RET activates the ERK/MAPK, the PI3K/AKT/mTOR and the JAK/STAT3 pathways. Here, we tested the efficacy of a JAK1/2- inhibitor,
AZD1480, in the in vitro and in vivo growth of
thyroid cancer cell lines expressing oncogenic RET.
Thyroid cancer cell lines harboring RET/PTC1 (TPC-1), RET M918T (MZ-CRC1) and RET C634W (TT) alterations, as well as TPC-1 xenografts, were treated with
JAK inhibitor,
AZD1480. This inhibitor led to growth inhibition and/or apoptosis of the
thyroid cancer cell lines in vitro, as well as to
tumor regression of TPC-1 xenografts, where it efficiently blocked STAT3 activation in
tumor and stromal cells. This inhibition was associated with decreased proliferation, decreased blood vessel density, coupled with increased
necrosis. However,
AZD1480 repressed the growth of STAT3- deficient TPC-1 cells in vitro and in vivo, demonstrating that its effects in this cell line were independent of STAT3 in the
tumor cells. In all cell lines, the
JAK inhibitor reduced phospho-Y1062 RET levels, and mTOR effector phospho-S6, while JAK1/2 downregulation by
siRNA did not affect cell growth nor RET and S6 activation. In conclusion,
AZD1480 effectively blocks proliferation and
tumor growth of activated RET-
thyroid cancer cell lines, likely through direct RET inhibition in
cancer cells as well as by modulation of the microenvironment (e.g. via JAK/phospho-STAT3 inhibition in endothelial cells). Thus,
AZD1480 should be considered as a therapeutic agent for the treatment of RET- activated
thyroid cancers.