Akt/mTOR Counteract the Antitumor Activities of Cixutumumab, an Anti-Insulin-like Growth Factor I Receptor Monoclonal Antibody

Department of Thoracic/Head and Neck Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
Molecular Cancer Therapeutics (Impact Factor: 5.68). 12/2011; 10(12):2437-48. DOI: 10.1158/1535-7163.MCT-11-0235
Source: PubMed


Recent reports have shown limited anticancer therapeutic efficacy of insulin-like growth factor receptor (IGF-1R)-targeted monoclonal antibodies (mAb), but the resistance mechanisms have not been completely identified. Because cooperation between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance to inhibitors of individual receptor tyrosine kinases, we investigated the involvement of EGFR signaling in resistance to IGF-1R mAb and the underlying mechanisms of action. Most head and neck squamous cell carcinoma (HNSCC) tissues had coexpression of total and phosphorylated IGF-1R and EGFR at high levels compared with paired adjacent normal tissues. Treatment with cixutumumab (IMC-A12), a fully humanized IgG1 mAb, induced activation of Akt and mTOR, resulting in de novo synthesis of EGFR, Akt1, and survivin proteins and activation of the EGFR pathway in cixutumumab-resistant HNSCC and non-small cell lung cancer (NSCLC) cells. Targeting mTOR and EGFR pathways by treatment with rapamycin and cetuximab (an anti-EGFR mAb), respectively, prevented cixutumumab-induced expression of EGFR, Akt, and survivin and induced synergistic antitumor effects in vitro and in vivo. These data show that resistance to IGF-1R inhibition by mAbs is associated with Akt/mTOR-directed enhanced synthesis of EGFR, Akt1, and survivin. Our findings suggest that Akt/mTOR might be effective targets to overcome the resistance to IGF-1R mAbs in HNSCC and NSCLC.

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    • "The IGF/IGF-1R pathway has also been shown to have extensive cross-talk with the estrogen receptor (ER), epidermal growth factor receptor (EGFR), and human epidermal growth factor receptor 2 (HER-2) signaling pathways and to play an important role in the resistance mechanisms of cytotoxic drugs and EGFR/HER-2–targeted agents[16]. More recent work also suggests a potential role for IGF-1R in the resistance to mTOR inhibitors[17] and RAF-MEK inhibitors[18]. "
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    ABSTRACT: Type I insulin-like growth factor receptor (IGF-1R) has long been recognized for its role in tumorigenesis and growth, but only recently have the tools for targeting the IGF pathway become available. More than 10 IGF/IGF-1R inhibitors have entered clinical trials, and these belong to three main classes: (1) monoclonal antibodies against IGF-1R, (2) monoclonal antibodies against IGF-1R ligands (IGF-1 and IGF-2), and (3) IGF-1R tyrosine kinase inhibitors. These IGF-1R-targeting agents share common effects on IGF-1R signaling but differ in mechanisms of action, spectrum of target inhibition, and pharmacological features. Clinical activity of IGF-1R inhibitors has been demonstrated with sustained responses in a small number of patients with select tumor types, such as Ewing sarcoma and thymoma. However, many large clinical trials involving patients with adult tumors, including non-small cell lung cancer, breast cancer, and pancreatic cancer, failed to show clinical benefit in the overall patient population. Possible reasons for failure include the complexity of the IGF-1R/insulin receptor system and parallel growth and survival pathways, as well as a lack of patient selection markers. While IGF-1R remains a valid target for selected tumor types, identification of predictive markers and rational combinations will be critical to success in future development.
    Ai zheng = Aizheng = Chinese journal of cancer 04/2013; 32(5). DOI:10.5732/cjc.012.10263 · 2.16 Impact Factor
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    • "Rapamycin is an inhibitor of mammalian target of rapamycin (mTOR) complex 1, a downstream signal transducer of IGF-1R, and has been extensively investigated in combination with IGF-1R inhibition in ES. The combination of rapamycin and cixutumumab demonstrated synergistic antitumor effects in vitro and in vivo in a Stage 2 study by the Pediatric Preclinical Testing Program (PPTP) [42, 43]. However, results of these combination studies have not been entirely consistent. "
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    ABSTRACT: The insulin-like growth factor 1 receptor (IGF-1R) has been considered an important therapeutic target in Ewing sarcoma (ES), generating a need to identify the subset of patients most likely to respond to IGF-1R inhibitors. We assessed IGF-1R expression in ES cell lines and patient tumors to understand the variable clinical responses to anti-IGF-1R therapy. Using ligand-binding displacement, we measured between 13,000 and 40,000 receptors per cell in ES cell lines. We used ELISA to quantify IGF-1R in patient tumors, which expressed 4.8% ± 3.7 to 20.0% ± 0.2 of the levels in a positive control cell line overexpressing IGF-1R. Flow cytometry showed markedly reduced IGF-1R expression in ES cell lines compared to a standard positive control cell line. The IGF1R gene was sequenced in 47 ES tumor samples and 8 ES cell lines; only one tumor sample showed a nonsynonymous mutation, R1353H, in a region with low functional impact. Finally, we assessed IGF-1R pathway activity in the ES stem cell (ESSC) population, to characterize its potential for resistance to anti-IGF-1R therapy, using Luminex technology. We found no significant differences in IGF-1R pathway activity between ESSCs and the total cell population. Overall, our findings suggest that IGF-1R as a therapeutic target in this sarcoma may require reevaluation.
    Sarcoma 01/2013; 2013(6):450478. DOI:10.1155/2013/450478
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    ABSTRACT: Mammalian target of rapamycin (mTOR) is a serine/threonine kinase that functions as a key regulatory protein in normal cell growth, survival, metabolism, development, and angiogenic pathways. Deregulation of these processes is a required hallmark of cancer, and dysregulation of mTOR signaling frequently occurs in a wide variety of malignancies, including lung cancer. Targeting of mTOR is thus an attractive strategy in the development of therapeutic agents against lung cancer. In this review, the mTOR-signaling pathway is described, highlighting opportunities for therapeutic intervention and biomarker analysis, and clinical trials in lung cancer including both non-small cell lung cancer and small cell lung cancer.
    Journal of thoracic oncology: official publication of the International Association for the Study of Lung Cancer 06/2012; 7(6):947-53. DOI:10.1097/JTO.0b013e31825581bd · 5.28 Impact Factor
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