TY - JOUR
T1 - Antitumor profile of the PI3K inhibitor ZSTK474 in human sarcoma cell lines
AU - Namatame, Nachi
AU - Tamaki, Naomi
AU - Yoshizawa, Yuya
AU - Okamura, Mutsumi
AU - Nishimura, Yumiko
AU - Yamazaki, Kanami
AU - Tanaka, Miwa
AU - Nakamura, Takuro
AU - Semba, Kentaro
AU - Yamori, Takao
AU - Yaguchi, Shin Ichi
AU - Dan, Shingo
N1 - Funding Information:
This work was supported in part by Practical Research for Innovative Cancer Control (16ck0106089s0203) from Japan Agency for Medical Research and Development, and a grant from National Cancer Center Research Development Fund (#29-A-7).
Publisher Copyright:
© 2018 Impact Journals LLC. All rights reserved.
PY - 2018/10/1
Y1 - 2018/10/1
N2 - Treatment of patients with advanced sarcoma remains challenging due to lack of effective medicine, with the development of novel drugs being of keen interest. A pan-PI3K inhibitor, ZSTK474, has been evaluated in clinical trials against a range of advanced solid tumors, with clinical benefit shown in sarcoma patients. In the present study, we developed a panel of 14 human sarcoma cell lines and investigated the antitumor effect of 24 anticancer agents including ZSTK474, other PI3K inhibitors, and those clinically used for sarcoma treatment. ZSTK474 exhibited a similar antiproliferative profile to other PI3K inhibitors but was clearly different from the other drugs examined. Indeed, ZSTK474 inhibited PI3K-downstream pathways, in parallel to growth inhibition, in all cell lines examined, showing proof-of-concept of PI3K inhibition. In addition, ZSTK474 induced apoptosis selectively in Ewing's sarcoma (RD-ES and A673), alveolar rhabdomyosarcoma (SJCRH30) and synovial sarcoma (SYO-1, Aska-SS and Yamato-SS) cell lines, all of which harbor chromosomal translocation and resulting oncogenic fusion genes, EWSR1-FLI1, PAX3-FOXO1 and SS18-SSX, respectively. Finally, animal experiments confirmed the antitumor activity of ZSTK474 in vivo, with superior efficacy observed in translocation-positive cells. These results suggest that ZSTK474 could be a promising drug candidate for treating sarcomas, especially those harboring chromosomal translocation.
AB - Treatment of patients with advanced sarcoma remains challenging due to lack of effective medicine, with the development of novel drugs being of keen interest. A pan-PI3K inhibitor, ZSTK474, has been evaluated in clinical trials against a range of advanced solid tumors, with clinical benefit shown in sarcoma patients. In the present study, we developed a panel of 14 human sarcoma cell lines and investigated the antitumor effect of 24 anticancer agents including ZSTK474, other PI3K inhibitors, and those clinically used for sarcoma treatment. ZSTK474 exhibited a similar antiproliferative profile to other PI3K inhibitors but was clearly different from the other drugs examined. Indeed, ZSTK474 inhibited PI3K-downstream pathways, in parallel to growth inhibition, in all cell lines examined, showing proof-of-concept of PI3K inhibition. In addition, ZSTK474 induced apoptosis selectively in Ewing's sarcoma (RD-ES and A673), alveolar rhabdomyosarcoma (SJCRH30) and synovial sarcoma (SYO-1, Aska-SS and Yamato-SS) cell lines, all of which harbor chromosomal translocation and resulting oncogenic fusion genes, EWSR1-FLI1, PAX3-FOXO1 and SS18-SSX, respectively. Finally, animal experiments confirmed the antitumor activity of ZSTK474 in vivo, with superior efficacy observed in translocation-positive cells. These results suggest that ZSTK474 could be a promising drug candidate for treating sarcomas, especially those harboring chromosomal translocation.
KW - Anticancer agent
KW - Cell line panel
KW - Oncogenic chromosomal translocation
KW - PI3K
KW - Sarcoma
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U2 - 10.18632/oncotarget.26216
DO - 10.18632/oncotarget.26216
M3 - Article
AN - SCOPUS:85054714117
SN - 1949-2553
VL - 9
SP - 35141
EP - 35161
JO - Oncotarget
JF - Oncotarget
IS - 80
ER -