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

Anderson JL, Park A, Akiyama R, Tap WD, Denny CT, Federman N - PLoS ONE (2015)

Bottom Line: 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.The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Division of Hematology/Oncology, Gwynne Hazen Cherry Memorial Laboratories, University of California, Los Angeles, Los Angeles, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus

PTEN and basal phospho-Akt levels in a panel of tumor cell lines.(A) Immunoblot analysis of PTEN, phospho-Akt (S473), total Akt, and actin in ES, OS, RMS, breast cancer (MCF-7), and prostate cancer (LNCaP) cell lines. (B) Known PI3K and MAPK pathway mutations in cell lines evaluated in A. ES, Ewing sarcoma; ERMS, embryonal rhabdomyosarcoma; DEL, deletion; INS, insertion.
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pone.0133610.g001: PTEN and basal phospho-Akt levels in a panel of tumor cell lines.(A) Immunoblot analysis of PTEN, phospho-Akt (S473), total Akt, and actin in ES, OS, RMS, breast cancer (MCF-7), and prostate cancer (LNCaP) cell lines. (B) Known PI3K and MAPK pathway mutations in cell lines evaluated in A. ES, Ewing sarcoma; ERMS, embryonal rhabdomyosarcoma; DEL, deletion; INS, insertion.

Mentions: We first assessed PTEN expression and basal levels of Akt phosphorylation in a panel of ES, OS, and RMS cell lines. The breast cancer cell line MCF-7 and prostate cancer cell line LNCaP were also included since they display increased Akt phosphorylation due the presence of PIK3CA and PTEN mutations, respectively. Akt phosphorylation was detected at varying levels in the majority of sarcoma cell lines examined, with higher levels observed in ES cell lines that lacked PTEN expression (Fig 1A). The ES cell line A673, which harbors a B-RAF mutation and thus expected to have less dependence on PI3K/Akt signaling, displayed low phospho-Akt levels. Conversely, the RMS cell line RD displayed high levels of Akt phosphorylation despite possessing a MAPK pathway mutation (Fig 1A and 1B). This is likely the result of the ability of the p110α isoform of PI3K to function as downstream effector of oncogenic RAS [25].


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

Anderson JL, Park A, Akiyama R, Tap WD, Denny CT, Federman N - PLoS ONE (2015)

PTEN and basal phospho-Akt levels in a panel of tumor cell lines.(A) Immunoblot analysis of PTEN, phospho-Akt (S473), total Akt, and actin in ES, OS, RMS, breast cancer (MCF-7), and prostate cancer (LNCaP) cell lines. (B) Known PI3K and MAPK pathway mutations in cell lines evaluated in A. ES, Ewing sarcoma; ERMS, embryonal rhabdomyosarcoma; DEL, deletion; INS, insertion.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4581723&req=5

pone.0133610.g001: PTEN and basal phospho-Akt levels in a panel of tumor cell lines.(A) Immunoblot analysis of PTEN, phospho-Akt (S473), total Akt, and actin in ES, OS, RMS, breast cancer (MCF-7), and prostate cancer (LNCaP) cell lines. (B) Known PI3K and MAPK pathway mutations in cell lines evaluated in A. ES, Ewing sarcoma; ERMS, embryonal rhabdomyosarcoma; DEL, deletion; INS, insertion.
Mentions: We first assessed PTEN expression and basal levels of Akt phosphorylation in a panel of ES, OS, and RMS cell lines. The breast cancer cell line MCF-7 and prostate cancer cell line LNCaP were also included since they display increased Akt phosphorylation due the presence of PIK3CA and PTEN mutations, respectively. Akt phosphorylation was detected at varying levels in the majority of sarcoma cell lines examined, with higher levels observed in ES cell lines that lacked PTEN expression (Fig 1A). The ES cell line A673, which harbors a B-RAF mutation and thus expected to have less dependence on PI3K/Akt signaling, displayed low phospho-Akt levels. Conversely, the RMS cell line RD displayed high levels of Akt phosphorylation despite possessing a MAPK pathway mutation (Fig 1A and 1B). This is likely the result of the ability of the p110α isoform of PI3K to function as downstream effector of oncogenic RAS [25].

Bottom Line: 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.The addition of NVP-AEW541 also further reduced phospho-Akt levels and more potently induced apoptosis compared to buparlisib treatment alone.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, Division of Hematology/Oncology, Gwynne Hazen Cherry Memorial Laboratories, University of California, Los Angeles, Los Angeles, California, United States of America.

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.

No MeSH data available.


Related in: MedlinePlus