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The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo.

ABSTRACT: This study focuses on determining whether the combination of NYP-BKM120 (BKM120) and RAD001 exerts enhanced therapeutic effect against lung cancer. The combination of BKM120 and RAD001 exerted synergistic inhibitory effects on the growth of lung cancer cells both in culture and in mouse xenograft model. This combination abrogated RAD001-induced Akt phosphorylation and exerted enhanced suppressive effect on 4EBP1 phosphorylation. Collectively, we suggest that the combination of RAD001 and BKM120 may be an effective regimen for treatment of lung cancer, hence warranting further evaluation of the combination in the clinic.

SUBMITTER: Ren H

PROVIDER: S-EPMC3433638 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo.

Ren Hui H Chen Mingwei M Yue Ping P Tao Hui H Owonikoko Taofeek K TK Ramalingam Suresh S SS Khuri Fadlo R FR Sun Shi-Yong SY

Cancer letters 20120707 2

This study focuses on determining whether the combination of NYP-BKM120 (BKM120) and RAD001 exerts enhanced therapeutic effect against lung cancer. The combination of BKM120 and RAD001 exerted synergistic inhibitory effects on the growth of lung cancer cells both in culture and in mouse xenograft model. This combination abrogated RAD001-induced Akt phosphorylation and exerted enhanced suppressive effect on 4EBP1 phosphorylation. Collectively, we suggest that the combination of RAD001 and BKM120 ...[more]

PMID: 22781393

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Project description:PURPOSE:To provide rationale for using phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathway inhibitors to treat rhabdomyosarcomas, a major cause of pediatric and adolescent cancer deaths. EXPERIMENTAL DESIGN:The prevalence of PI3K/MAPK pathway activation in rhabdomyosarcoma clinical samples was assessed using immunohistochemistry. Compensatory signaling and cross-talk between PI3K/MAPK pathways was determined in rhabdomyosarcoma cell lines following p110? short hairpin RNA-mediated depletion. Pharmacologic inhibition of reprogrammed signaling in stable p110? knockdown lines was used to determine the target-inhibition profile inducing maximal growth inhibition. The in vitro and in vivo efficacy of inhibitors of TORC1/2 (AZD8055), MEK (AZD6244), and P13K/mTOR (NVP-BEZ235) was evaluated alone and in pairwise combinations. RESULTS:PI3K pathway activation was seen in 82.5% rhabdomyosarcomas with coactivated MAPK in 36% and 46% of alveolar and embryonal subtypes, respectively. p110? knockdown in cell lines over the short and long term was associated with compensatory expression of other p110 isoforms, activation of the MAPK pathway, and cross-talk to reactivate the PI3K pathway. Combinations of PI3K pathway and MAP-ERK kinase (MEK) inhibitors synergistically inhibited cell growth in vitro. Treatment of RD cells with AZD8055 plus AZD6244 blocked reciprocal pathway activation, as evidenced by reduced AKT/ERK/S6 phosphorylation. In vivo, the synergistic effect on growth and changes in pharmacodynamic biomarkers was recapitulated using the AZD8055/AZD6244 combination but not NVP-BEZ235/AZD6244. Pharmacokinetic analysis provided evidence of drug-drug interaction with both combinations. CONCLUSIONS:Dual PI3K/MAPK pathway activation and compensatory signaling in both rhabdomyosarcoma subtypes predict a lack of clinical efficacy for single agents targeting either pathway, supporting a therapeutic strategy combining a TORC1/2 with a MEK inhibitor.

Dataset Information

The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo.

Publications

The combination of RAD001 and NVP-BKM120 synergistically inhibits the growth of lung cancer in vitro and in vivo.

Similar Datasets

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