TY - JOUR
T1 - Expression and role of TYRO3 and AXL as potential therapeutical targets in leiomyosarcoma
AU - Dantas-Barbosa, Carmela
AU - Lesluyes, Tom
AU - Le Loarer, François
AU - Chibon, Fréderic
AU - Treilleux, Isabelle
AU - Coindre, Jean Michel
AU - Meeus, Pierre
AU - Brahmi, Mehdi
AU - Bally, Olivia
AU - Ray-Coquard, Isabelle
AU - Sunyach, Marie Pierre
AU - Le Cesne, Axel
AU - Mir, Olivier
AU - Bonvalot, Sylvie
AU - Toulmonde, Maud
AU - Italiano, Antoine
AU - Saintigny, Pierre
AU - Jean-Denis, Myriam
AU - Ducimetiere, Francoise
AU - Ranchere, Dominique
AU - El Sayadi, Hiba
AU - Alberti, Laurent
AU - Blay, Jean Yves
N1 - Publisher Copyright:
© The Author(s) named above 2017.
PY - 2017/1/1
Y1 - 2017/1/1
N2 - Background: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS. Methods: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro. Results: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS. Conclusions: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS.
AB - Background: Leiomyosarcoma (LMS) are 15% of adult sarcomas and remain seldom curable in metastatic phase. The TAM receptors and their ligands are overexpressed or activated in multiple malignancies, including LMS. Methods: The TAM receptor and ligand expression was evaluated in LMS cell lines and 358 sarcoma samples by either gene expression or immunohistochemistry. TYRO3 and AXL were knocked down. Crizotinib and foretinib were investigated in vitro. Results: High expression of TYRO3 and AXL was detected in LMS cell lines. TYRO3 or AXL gene knockdown reduced cell proliferation/colony formation. Crizotinib and foretinib decreased TYRO3 and AXL phosphorylation, apoptosis, G2/arrest and reduced colony formation. Immunohistochemistry performed in 107 sarcomas showed higher expression of TYRO3 and GAS6 in LMS vs other sarcomas and nuclear TYRO3 only in LMS. Microarray gene expression performed in 251 sarcomas revealed significantly higher expression of TYRO3 and GAS6 in LMS than other sarcomas. Leiomyosarcoma patients with high expression of GAS6 or PROS1 present a significantly worse PFS. Conclusions: Leiomyosarcoma patients, especially those whom develop metastasis, express higher levels of TYRO3 and GAS6. Crizotinib and foretinib showed effective antitumour activity in LMS through TYRO3 and AXL deactivation indicating that clinical trials using TYRO3 and AXL inhibitors are warranted in advanced LMS.
KW - AXL
KW - GAS6
KW - Leiomyosarcoma
KW - Sarcoma
KW - TAM receptors
KW - TYRO3
KW - Tyrosine kinase inhibitor
UR - http://www.scopus.com/inward/record.url?scp=85038389233&partnerID=8YFLogxK
U2 - 10.1038/bjc.2017.354
DO - 10.1038/bjc.2017.354
M3 - Article
C2 - 29024938
AN - SCOPUS:85038389233
SN - 0007-0920
VL - 117
SP - 1787
EP - 1797
JO - British Journal of Cancer
JF - British Journal of Cancer
IS - 12
ER -