Combination of PI3K/mTOR inhibition demonstrates efficacy in human chordoma.
BACKGROUND
Chordomas are rare tumors of the axial skeleton for which surgical resection remains the most reliable means of cure. PI-103 is a inhibitor of PI3K/AKT and mTOR activation. This study aims to determine whether the PI3K/mTOR pathway was active in chordomas and whether their inhibition could lead to decreased proliferation and increased apoptosis.


METHODS
Thirteen human chordoma were tested for activation of the PI3K/mTOR pathway. The human chordoma cell line UCH-1 was treated with increasing doses of PI-103. Inhibition of AKT and mTOR was examined and assays assessing proliferation and apoptosis were performed.


RESULTS
The chordoma specimen demonstrated activation of the PI3K/mTOR pathway. PI-103 inhibited the AKT and mTOR activation in the UCH-1 cell line. PI-103 inhibited proliferation and induced apoptosis in UCH-1.


CONCLUSIONS
The PI3K/AKT and mTOR signaling pathway is constitutively activated in chordoma. PI-103 decreases proliferation and induces apoptosis in the UCH-1 via inhibition of the PI3K/mTOR pathway.
Schwab
Joseph
J
Department of Orthopedic Surgery, Section of Orthopedic Oncology, Sarcoma Research Laboratory, Massachusetts General Hospital, Boston, MA 02114, U.S.A. jhschwab@partners.org
Antonescu
Cristina
C
Boland
Patrick
P
Healey
John
J
Rosenberg
Andrew
A
Nielsen
Petur
P
Iafrate
John
J
Delaney
Thomas
T
Yoon
Sam
S
Choy
Edwin
E
Harmon
David
D
Raskin
Kevin
K
Yang
Cao
C
Mankin
Henry
H
Springfield
Dempsey
D
Hornicek
Francis
F
Duan
Zhenfeng
Z
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D002817:Chordoma / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D005663:Furans / Q000627:therapeutic use*; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000737:chemistry / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors* / Q000378:metabolism; D011725:Pyridines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*; D058570:TOR Serine-Threonine Kinases; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000970:Antineoplastic Agents; D002945:Cisplatin; D004317:Doxorubicin; D005663:Furans; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011725:Pyridines; D011743:Pyrimidines; D058570:TOR Serine-Threonine Kinases; C522973:PI103; C546842:MTOR protein, human