Open AccessSynergistic antitumour activity of RAF 265 and ZSTK 474 on human TT medullary thyroid cancer cells
Author(s) -
Bertazza Loris,
Barollo Susi,
Radu Claudia Maria,
Cavedon Elisabetta,
Simioni Paolo,
Faggian Diego,
Plebani Mario,
Pelizzo Maria Rosa,
Rubin Beatrice,
Boscaro Marco,
Pezzani Raffaele,
Mian Caterina
Publication year - 2015
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/jcmm.12612
Subject(s) - medullary thyroid cancer , cfu gm , medullary cavity , thyroid cancer , chemistry , cancer , cancer research , medicine , biology , microbiology and biotechnology , stem cell , progenitor cell
Medullary thyroid cancer ( MTC ) is an aggressive malignancy responsible for up to 14% of all thyroid cancer‐related deaths. It is characterized by point mutations in the rearranged during transfection ( RET ) proto‐oncogene. The activated RET kinase is known to signal via extracellular signal regulated kinase ( ERK ) and phosphoinositide 3‐kinase ( PI 3K), leading to enhanced proliferation and resistance to apoptosis. In the present work, we have investigated the effect of two serine/threonine‐protein kinase B‐Raf (BRAF) inhibitors ( RAF 265 and SB 590885), and a PI 3K inhibitor ( ZSTK 474), on RET ‐mediated signalling and proliferation in a MTC cell line ( TT cells) harbouring the RETC 634W activating mutation. The effects of the inhibitors on VEGFR 2, PI 3K/Akt and mitogen‐activated protein kinases signalling pathways, cell cycle, apoptosis and calcitonin production were also investigated. Only the RAF 265+ ZSTK 474 combination synergistically reduced the viability of treated cells. We observed a strong decrease in phosphorylated VEGFR 2 for RAF 265+ ZSTK 474 and a signal reduction in activated Akt for ZSTK 474. The activated ERK signal also decreased after RAF 265 and RAF 265+ ZSTK 474 treatments. Alone and in combination with ZSTK 474, RAF 265 induced a sustained increase in necrosis. Only RAF 265, alone and combined with ZSTK 474, prompted a significant drop in calcitonin production. Combination therapy using RAF 265 and ZSTK 47 proved effective in MTC , demonstrating a cytotoxic effect. As the two inhibitors have been successfully tested individually in clinical trials on other human cancers, our preclinical data support the feasibility of their combined use in aggressive MTC .