Evaluation of In Vitro Activity of the Class I PI3K Inhibitor Buparlisib (BKM120) in Pediatric Bone and Soft Tissue Sarcomas.

Jennifer L Anderson,Noah Federman,Christopher T Denny,William D Tap,Ryan Akiyama,Ann Park,David M Loeb

doi:10.1371/journal.pone.0133610

Abstract

Pediatric bone and soft tissue sarcomas often display increased Akt phosphorylation through up regulation of insulin-like growth factor (IGF1) signaling. Additionally, Akt signaling has been linked to resistance to IGF1 receptor (IGF1R) and mTOR (mammalian target of rapamycin) inhibitors in sarcoma, further demonstrating the role of Akt in tumor survival. This suggests targeting components of the PI3K/Akt pathway may be an effective therapeutic strategy. Here, we investigated the in vitro activity of the pan-class I PI3K inhibitor buparlisib (BKM120) in pediatric bone and soft tissue sarcomas. Buparlisib inhibited activation of Akt and signaling molecules downstream of mTORC1 (mTOR complex 1) in Ewing sarcoma, osteosarcoma, and rhabdomyosarcoma cell lines. Anti-proliferative effects were observed in both anchorage dependent and independent conditions and apoptosis was induced within 24 hours of drug treatment. Buparlisib demonstrated cytotoxicity as a single agent, but was found to be more effective when used in combination. Synergy was observed when buparlisib was combined with the IGF1R inhibitor NVP-AEW541 and the mTORC1 inhibitor rapamycin. The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone. Additionally, the combination of buparlisib with the MEK1/2 inhibitor trametinib resulted in synergy in sarcoma cell lines possessing MAPK pathway mutations. Taken together, these data indicate buparlisib could be a novel therapy for the treatment of pediatric bone and soft tissue sarcomas.

Highlights

Pediatric bone and soft tissue sarcomas have an overall 5-year survival rate near 60% that has plateaued with current treatments
Akt phosphorylation was detected at varying levels in the majority of sarcoma cell lines examined, with higher levels observed in Ewing sarcoma (ES) cell lines that lacked PTEN expression (Fig 1A)
Buparlisib inhibits anchorage dependent and independent growth of sarcoma cell lines After demonstrating that buparlisib inhibits phosphoinositide 3-kinase (PI3K)/Akt signaling, we examined its anti-proliferative effects in a panel of sarcoma cell lines

Summary

Introduction

Pediatric bone and soft tissue sarcomas have an overall 5-year survival rate near 60% that has plateaued with current treatments. While pediatric sarcomas have diverse underlying mutations, they often converge on common signaling pathways that regulate cellular growth and survival. Both Ewing sarcoma and alveolar rhabdomyosarcoma display a dependence on insulin-like growth factor (IGF) signaling despite harboring distinct oncogenic fusions [1]. MTOR (mammalian target of rapamycin) inhibition induces activation of Akt in cancer cell lines and patient tumors [10, 11]. This indicates a dependence on Akt signaling for cell survival as well as escape from targeted therapies

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Conclusion