Deciphering the Role of Insulin-Like Growth Factor-I Receptor in Trastuzumab Resistance

Nahta, Rita

doi:10.1155/2012/648965

Cited by 19 publications

(16 citation statements)

References 49 publications

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“…IGF-1R as a therapeutic target in breast cancer is currently being evaluated in a number clinical trials, especially as part of strategies to overcome resistance to endocrine therapy for ER+ breast cancer and trastuzumab in HER2 positive disease [40, 41]. In this trial, we observed a prolonged disease stabilization in one patient with ER+/HER2+ breast cancer, who was treated primarily with Cixutumumab alone since cycle 1 day 15 after temsirolimus was discontinued due to toxicity, demonstrating the potential activity of IGF-IR inhibition in this tumor type.…”

Section: Discussionmentioning

confidence: 99%

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer

Cynthia

Suman

Goetz

et al. 2013

Breast Cancer Res Treat

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The mammalian target of rapamycin (mTOR) plays a critical role in promoting tumor cell growth and is frequently activated in breast cancer. In preclinical studies, the antitumor activity of mTOR inhibitors is attenuated by feedback up-regulation of AKT mediated in part by Insulin-like growth factor type 1 receptor (IGF-1R). We designed a phase I trial to determine the maximum-tolerated dose (MTD) and pharmacodynamic effects of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer refractory to standard therapies. A 3 + 3 Phase I design was chosen. Temsirolimus and Cixutumumab were administered intravenously on days 1, 8, 15, and 22 of a 4-week cycle. Of the 26 patients enrolled, four did not complete cycle 1 because of disease progression (n = 3) or comorbid condition (n = 1) and were replaced. The MTD was determined from the remaining 22 patients, aged 34–72 (median 48) years. Most patients (86 %) had estrogen receptor positive cancer. The median number of prior chemotherapy regimens for metastatic disease was 3. The MTD was determined to be Cixutumumab 4 mg/kg and temsirolimus 15 mg weekly. Dose-limiting toxicities (DLTs) included mucositis, neutropenia, and thrombocytopenia. Other adverse events included grade 1/2 fatigue, anemia, and hyperglycemia. No objective responses were observed, but four patients experienced stable disease that lasted for at least 4 months. Compared with baseline, there was a significant increase in the serum levels of IGF-1 (p < 0.001) and IGFBP-3 (p = 0.019) on day 2. Compared with day 2, there were significant increases in the serum levels of IGF-1 (p < 0.001), IGF-2 (p = 0.001), and IGFBP-3 (p = 0.019) on day 8. A phase II study in women with metastatic breast cancer is ongoing.

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Section: Discussionmentioning

confidence: 99%

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer

Cynthia

Suman

Goetz

et al. 2013

Breast Cancer Res Treat

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“…Several studies have described the signaling interactions between the members of the ErbB/HER family of tyrosine kinase receptors and have implicated the IGF-1R pathway in the development of resistance towards targeted therapies, including towards trastuzumab [7,8], EGFR tyrosine kinase inhibitors, and tamoxifen [9]. Therefore, targeting IGF-1R as well as members of the epidermal growth factor receptor family (specifically, EGFR and HER2) is an attractive therapeutic strategy for the treatment of primary breast cancer.…”

Section: Introductionmentioning

confidence: 99%

Positive Expression of Insulin-Like Growth Factor-1 Receptor Is Associated with a Positive Hormone Receptor Status and a Favorable Prognosis in Breast Cancer

et al. 2014

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PurposeInsulin-like growth factor 1 receptor (IGF-1R) is commonly expressed in primary breast cancers. Understanding the role of IGF-1R signaling in the different subtypes of breast cancer is important because each subtype has a different outcome and requires different treatment modalities. However, the precise biological significance of IGF-1R expression in cancer cells is still unclear. In this study, we examined the expression of IGF-1R in the different molecular subtypes of breast cancer. The effects of IGF-1R expression on the survival rates and outcomes of breast cancer were also examined.MethodsIGF-1R expression was evaluated immunohistochemically in tissue microarray blocks constructed from 1,198 invasive breast cancer samples collected from six medical institutions. IGF-1R expression was interpreted according to the human epidermal growth factor receptor 2 (HER2)/neu immunohistochemistry scoring system. Scores of 2+ and 3+ were considered positive.ResultsPositive IGF-1R expression was observed in 65.4% of invasive breast cancer samples. IGF-1R expression was detected in all cancer subtypes (luminal A, 84.4%; luminal B, 75.9%; HER2, 21.2%; triple-negative, 46.6%) and was found to be associated with a positive hormone receptor status and the absence of HER2 amplification (p<0.001). Positive IGF-1R expression was significantly associated with high survival rates (p=0.014). However, a multivariate analysis revealed that the expression levels of IGF-1R did not achieve statistical significance. In the triple-negative cancer subtype, IGF-1R expression was found to be associated with a lower disease-free survival rate (p=0.031).ConclusionPositive IGF-1R expression is associated with a favorable prognosis in breast cancer. IGF-1R is frequently expressed in the luminal A/B subtypes of breast cancer, and its expression is related to the hormone receptor status.

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“…Several signaling molecules appear to activate cross-talk to HER2, including insulin-like growth factor-I receptor (IGF-IR), hepatocyte growth factor (HGF) and its receptor Met, growth differentiation factor 15 (GDF15), and members of the erbB family. We have recently reviewed the literature supporting IGF-IR cross-talk and/or overexpression in the development of trastuzumab resistance [81]. Lu et al [82] first demonstrated that increased IGF-IR signaling due to stable overexpression of IGF-IR in SKBR3 cells can abrogate trastuzumab-mediated G1 arrest.…”

Section: Trastuzumab: Potential Mechanisms Of Resistancementioning

confidence: 99%

“…IGF-IR signaling was inhibited using IGF-binding protein (IGFBP) 3, which restored the growth inhibitory activity of trastuzumab [82, 83]. We and others [81, 84–86] have shown that IGF-IR and HER2 can interact, facilitating cross-talk such that IGF-I induces phosphorylation of HER2, and IGF-IR inhibition reduces HER2 phosphorylation. IGF-IR/HER2 interactions have been reported in both models of acquired trastuzumab resistance [81, 85, 86], as well as in BT474 and MCF7/HER2 stable transfectant, which are sensitive to trastuzumab [84].…”

Section: Trastuzumab: Potential Mechanisms Of Resistancementioning

confidence: 99%

Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing Breast Cancer

Nahta

2012

ISRN Oncology

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The past decade of research into HER2-overexpressing breast cancer has provided significant insight into the mechanisms by which HER2 signaling drives tumor progression, as well as potential mechanisms by which cancer cells escape the anticancer activity of HER2-targeted therapy. Many of these preclinical findings have been translated into clinical development, resulting in novel combinations of HER2-targeted therapies and combinations of trastuzumab plus inhibitors of resistance pathways. In this paper, we will discuss proposed mechanisms of trastuzumab resistance, including epitope masking, cross signaling from other cell surface receptors, hyperactive downstream signaling, and failure to induce antibody-dependent cellular cytotoxicity. In addition, we will discuss the molecular mechanisms of action of dual HER2 inhibition, specifically the combination of trastuzumab plus lapatinib or trastuzumab with pertuzumab. We will also discuss data supporting therapeutic combinations of trastuzumab with agents targeted against molecules implicated in trastuzumab resistance. The roles of insulin-like growth factor-I receptor and the estrogen receptor are discussed in the context of resistance to HER2-targeted therapies. Finally, we will examine the major issues that need to be addressed in order to translate these combinations from the bench to the clinic, including the need to establish relevant biomarkers to select for those patients who are most likely to benefit from a particular drug combination.

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Deciphering the Role of Insulin-Like Growth Factor-I Receptor in Trastuzumab Resistance

Cited by 19 publications

References 49 publications

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer

A phase I trial of the IGF-1R antibody Cixutumumab in combination with temsirolimus in patients with metastatic breast cancer

Positive Expression of Insulin-Like Growth Factor-1 Receptor Is Associated with a Positive Hormone Receptor Status and a Favorable Prognosis in Breast Cancer

Molecular Mechanisms of Trastuzumab-Based Treatment in HER2-Overexpressing Breast Cancer

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