IGF-1R and mTOR Blockade: Novel Resistance Mechanisms and Synergistic Drug Combinations for Ewing Sarcoma

• Published in: JNCI : Journal of the National Cancer Institute Vol. 108; no. 12; p. djw182
• Main Authors: Lamhamedi-Cherradi, Salah-Eddine, Menegaz, Brian A, Ramamoorthy, Vandhana, Vishwamitra, Deeksha, Wang, Ying, Maywald, Rebecca L, Buford, Adriana S, Fokt, Izabela, Skora, Stanislaw, Wang, Jing, Naing, Aung, Lazar, Alexander J, Rohren, Eric M, Daw, Najat C, Subbiah, Vivek, Benjamin, Robert S, Ratan, Ravin, Priebe, Waldemar, Mikos, Antonios G, Amin, Hesham M, Ludwig, Joseph A
• Format: Journal Article
• Language: English
• Published: United States Oxford University Press 01-12-2016
• Subjects: Adenosine Triphosphatases - antagonists & inhibitors; Adenosine Triphosphatases - metabolism; Animals; Antibodies, Monoclonal - administration & dosage; Antineoplastic Combined Chemotherapy Protocols - pharmacology; Antineoplastic Combined Chemotherapy Protocols - therapeutic use; Bone Neoplasms - drug therapy; Bone Neoplasms - metabolism; Cation Transport Proteins - antagonists & inhibitors; Cation Transport Proteins - metabolism; Cell Line, Tumor; Copper-transporting ATPases; Drug Resistance, Neoplasm; Drug Synergism; Humans; Imidazoles - administration & dosage; Insulin Receptor Substrate Proteins - metabolism; Male; Mice; Mice, SCID; Neoplasm Transplantation; Nucleocytoplasmic Transport Proteins - metabolism; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphatidylinositol 3-Kinase - antagonists & inhibitors; Phosphatidylinositol 3-Kinase - metabolism; Protein Array Analysis; Pyrazines - administration & dosage; Pyrimidines - administration & dosage; Pyrroles - administration & dosage; Receptors, Somatomedin - antagonists & inhibitors; Sarcoma, Ewing - drug therapy; Sarcoma, Ewing - metabolism; Sirolimus - administration & dosage; Sirolimus - analogs & derivatives; STAT3 Transcription Factor - metabolism; TOR Serine-Threonine Kinases - antagonists & inhibitors; Up-Regulation
• ISSN: 0027-8874; 1460-2105
• DOI: 10.1093/jnci/djw182

Therapies cotargeting insulin-like growth factor receptor 1 (IGF-1R) and mammalian target of rapamycin (mTOR) have demonstrated remarkable, albeit short-lived, clinical responses in a subset of Ewing sarcoma (ES) patients. However, the mechanisms of resistance and applicable strategies for overcoming drug resistance to the IGF-1R/mTOR blockade are still undefined.
To elucidate predominant mechanism(s) of acquired drug resistance while identifying synergistic drug combinations that improve clinical efficacy, we generated more than 18 ES cell lines resistant to IGF-1R- or mTOR-targeted therapy. Two small-molecule inhibitors of IGF-1R were chosen, NVP-ADW-742 (IGF-1R-selective) and OSI-906 (a dual IGF-1R/insulin receptor alpha [IR-α] inhibitor). Reverse-phase protein lysate arrays (RPPAs) revealed proteomic changes linked to IGF-1R/mTOR resistance, and selected proteins were validated in cell-based assays, xenografts, and within human clinical samples. All statistical tests were two-sided.
Novel mechanisms of resistance (MOR) emerged after dalotuzumab-, NVP-ADW-742-, and OSI-906-based targeting of IGF-1R. MOR to dalotuzumab included upregulation of IRS1, PI3K, and STAT3, as well as p38 MAPK, which was also induced by OSI-906. pEIF4E(Ser209), a key regulator of Cap-dependent translation, was induced in ridaforolimus-resistant ES cell lines. Unique drug combinations targeting IGF-1R and PI3K-alpha or Mnk and mTOR were synergistic in vivo and vitro (P < .001) as assessed respectively by Mantel-Cox and isobologram testing.
We discovered new druggable targets expressed by chemoresistant ES cells, xenografts, and relapsed human tumors. Joint suppression of these newfound targets, in concert with IGF-1R or mTOR blockade, should improve clinical outcomes.