Insulin Receptor A and IGF-IR in AML – Response
Authors: Andrea E. Wahner Hendrickson, Paul Haluska, Charles Erlichman, Marco Gottardis, Joan E. Carboni, Judith E. Karp, Scott H. Kaufmann
Journal: Cancer Research (2010)

We applaud Chapuis and coworkers for recently showing an autocrine loop involving insulin-like growth factor I (IGF-I) and its receptor (IGF-IR) in acute myelogenous leukemia (AML). Although these studies identify IGF-IR as a potential therapeutic target, they do not address the contribution of insulin receptor isoform A (InsR-A) to AML. Doepfner and colleagues have reported that InsR is overexpressed on 85% of primary AML samples (1), and we have shown that this is exclusively InsR-A. Importantly, InsR seems to contribute to AML cell proliferation independent of IGF-IR, as evidenced by the equal antiproliferative effects of selective InsR and IGF-IR siRNAs in U937 cells (1). As we and others (1) have shown, certain AML lines and clinical samples also express IGF2, a high-affinity ligand for both IGF-IR and InsR-A. Collectively, these results raise the possibility that InsR-initiated signaling might contribute to the resistance observed by Chapuis in 30% of AML specimens treated with anti–IGF-IR antibody. Moreover, even AML specimens that respond to IGF-IR antibodies in vitro might need to be considered in light of emerging evidence that upregulated InsR-A signaling renders cells resistant to anti–IGF-IR therapy in vivo (2, 3). These observations provide a strong rationale for targeting both IGF-IR and InsR.Chapuis and colleagues question whether signaling by IGF-IR or InsR contributes to extracellular signal-regulated kinase (ERK) activation in AML. The data in our article show that IGF-I and Ins induce ERK phosphorylation when added to serum-depleted cells, but ERK remains phosphorylated in serum-treated cells exposed to BMS-536924 concentrations that inhibit IGF-IR/InsR activity and Akt phosphorylation. Thus, IGF-IR and InsR can contribute to ERK activation, but other signaling molecules clearly contribute as well.Chapuis and colleagues also suggest that BMS-536924–induced apoptosis might represent an off-target effect. Interestingly, the structurally distinct IGF-IR (and at higher concentrations InsR) inhibitor NVP-AEW541 also induces apoptosis in AML cell lines and clinical samples (1). Further studies are required to determine whether this reflects inhibition of IGF-IR and InsR or another target.Finally, Chapuis and colleagues speculate that IGF-IR/InsR inhibitors might induce more hyperglycemia than anti–IGF-IR antibodies. Contrary to this view, emerging clinical data show that hyperglycemia, the most common adverse event with the anti–IGF-IR antibody figitumumab (4), might actually be less problematic with IGF-IR/InsR kinase inhibitors given on a daily basis (5), perhaps due to their shorter serum half-lives. Thus, studies that assess both the efficacy and the toxicity of the two approaches in AML are awaited with interest.See the original Letter to the Editor, p. 7010.M. Gottardis and J.M. Carboni are employed by Bristol-Myers Squibb. P. Haluska has received research funding from and has served as a consultant for Bristol-Myers Squibb.