Abstract
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.
Highlights
Sarcomas are rare malignant tumors of mesenchymal origin, such as muscle, fat, bone and other connective tissues, with > 50 different subtypes reported to date [1]
We developed a panel of 14 human sarcoma cell lines and investigated the antitumor effect of 24 anticancer agents including ZSTK474, other phosphatidylinositol-3 kinase (PI3K) inhibitors, and those clinically used for sarcoma treatment
We characterized the antitumor profile of PI3K inhibitors, in particular ZSTK474 which we developed, against sarcomas in preclinical models by exploiting a panel of sarcoma cell lines derived from various origin; in this respect, effects on tumor growth, Figure 5: Effect on PI3K-downstream signaling pathway, apoptosis progression, transcriptional activity of EWSR1FLI1 and protein expression of Id2 upon treatment with ZSTK474 in Ewing’s sarcoma cell lines. (A, B) RD-ES cells (A) and A673 cells (B) were treated with ZSTK474 at the specified concentrations for the indicated time
Summary
Sarcomas are rare malignant tumors of mesenchymal origin, such as muscle, fat, bone and other connective tissues, with > 50 different subtypes reported to date [1]. There are two genetically characterized groups in sarcomas [4, 5]; one is characterized by a specific chromosomal translocation event on a background of relatively few other chromosomal changes, which is represented by Ewing’s sarcoma (ES) accompanied by the fusion of the EWSR1 (Ewing sarcoma region 1, called EWS) gene and one of the ETS transcriptional factor genes (FLI1 or ERG) [6] and synovial sarcoma (SS) accompanied by the fusion of the SS18 (Synovial Sarcoma Translocation, Chromosome 18, called SYT) gene and one of the SSX (Synovial Sarcoma, X Breakpoint) genes (SSX1, SSX2 or SSX4) [7,8,9] These www.oncotarget.com fusion gene products have a strong transformation activity, with the growth and survival of the cells containing these become exclusively dependent on the particular fusion [10,11,12]. Pazopanib was the first molecularly targeted agent approved for sarcoma treatment on the basis of modest benefit shown in the PALETTE study [17], with other small molecule inhibitors being examined in both preclinical and early phase clinical trials [18,19,20,21]
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