Dual blockade of the PI3K/AKT/mTOR (AZD8055) and RAS/MEK/ERK (AZD6244) pathways synergistically inhibits rhabdomyosarcoma cell growth in vitro and in vivo.
View/ Open
Date
2013-08-05ICR Author
Author
Renshaw, J
Taylor, KR
Bishop, R
Valenti, M
De Haven Brandon, A
Gowan, S
Eccles, SA
Ruddle, RR
Johnson, LD
Raynaud, FI
Selfe, JL
Thway, K
Pietsch, T
Pearson, AD
Shipley, J
Type
Journal Article
Metadata
Show full item recordAbstract
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 p110α short hairpin RNA-mediated depletion. Pharmacologic inhibition of reprogrammed signaling in stable p110α 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. p110α 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.
Subject
Cell Line, Tumor
Animals
Humans
Rhabdomyosarcoma
Disease Models, Animal
Morpholines
Benzimidazoles
Mitogen-Activated Protein Kinases
Antineoplastic Agents
Xenograft Model Antitumor Assays
Signal Transduction
Enzyme Activation
Drug Synergism
Female
Proto-Oncogene Proteins p21(ras)
Proto-Oncogene Proteins c-akt
Gene Knockdown Techniques
Phosphatidylinositol 3-Kinases
Class I Phosphatidylinositol 3-Kinases
TOR Serine-Threonine Kinases
Research team
Cancer Pharmacology & Stress Response (CPSR)
Clinical Pharmacology & Trials (including Drug Metabolism & Pharmacokinetics Group)
Tumour Biology & Metastasis
Paediatric Drug Development and Clinical Trials
Glioma Team
Sarcoma Molecular Pathology
Language
eng
Date accepted
2013-07-30
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2013, 19 (21), pp. 5940 - 5951
Publisher
AMER ASSOC CANCER RESEARCH