Feedback Mechanisms Promote Cooperativity for Small Molecule Inhibitors of Epidermal and Insulin-Like Growth Factor Receptors

Buck, Elizabeth; Eyzaguirre, Alexandra; Rosenfeld-Franklin, Maryland; Thomson, Stuart; Mulvihill, Mark J.; Barr, Sharon; Brown, Eric N.; O'Connor, Mathew; Yao, Yan; Pachter, Jonathan A.; Miglarese, Mark; Epstein, David; Iwata, Kenneth K.; Haley, John D.; Gibson, Neil W.; Ji, Qunsheng

doi:10.1158/0008-5472.can-07-6720

Cited by 182 publications

(174 citation statements)

References 33 publications

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“…Therefore, our findings indicate that, following blockade of IGF-1R signaling, hepatoma cells are able to switch from IGF-1R to EGFR dependency to maintain cell growth and AKT phosphorylation. During the preparation of this article, an adaptive up-regulation of the EGFR pathway in response to IGF-1R inhibition with small TKIs has been reported in ovarian and colon cancer cells (34,35). A reciprocal regulation seems not to occur in hepatoma cells because we did not observe any stimulating effect of gefitinib on IGF-1R signaling after short-term and even long-term exposures to this drug.…”

Section: Discussionmentioning

confidence: 53%

Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

Desbois-Mouthon

Baron

Eggelpoël

et al. 2009

Clinical Cancer Research

137

109

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Purpose: The insulin-like growth factor (IGF) signaling axis is frequently dysregulated in hepatocellular carcinoma (HCC). Therefore, we investigated whether the specific targeting of the IGF type 1 receptor (IGF-1R) might represent a new therapeutic approach for this tumor. Experimental Design: Total and phosphorylated levels of IGF-1R were measured in 21 paired samples of human HCCs and adjacent nontumoral livers using ELISA. The antineoplastic potency of a novel anti-IGF-1R antibody, AVE1642, was examined in five human hepatoma cell lines. Results: Overexpression of IGF-1R was detected in 33% of HCCs and increased activation of IGF-1R was observed in 52% of tumors. AVE1642 alone had moderate inhibitory effects on cell viability. However, its combination with gefitinib, an epidermal growth factor receptor (EGFR) inhibitor, induced supra-additive effects in all cell lines that were associated with cell cycle blockage and inhibition of AKT phosphorylation. The combination of AVE1642 with rapamycin also induced a synergistic reduction of viability and of AKT phosphorylation. Of marked interest, AVE1642 alone up-regulated the phosphorylated and total levels of HER3, the main partner of EGFR, and AVE1642-induced phosphorylation of HER3 was prevented by gefitinib. Moreover, the down-regulation of HER3 expression with siRNA reduced AKT phosphorylation and increased cell sensitivity to AVE1642. Conclusions: These findings indicate that hepatoma cells overcome IGF-1R inhibition through HER3 activation in an EGFR-dependent mechanism, and that HER3 represents a critical mediator in acquired resistance to anti-IGF-1R therapy. These results provide a strong rational for targeting simultaneously EGFR and IGF-1R in clinical trials for HCC]. (Clin Cancer Res 2009;15(17):5445-56)

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Section: Discussionmentioning

confidence: 53%

Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

Desbois-Mouthon

Baron

Eggelpoël

et al. 2009

Clinical Cancer Research

137

109

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“…In squamous epidermoid carcinomas with amplified EGFR, acquired resistance to the EGFR inhibitor gefitinib was explained by reduced expression of IGFBP-3 and IGFBP-4, both of which negatively modulate IGF1R by sequestering the IGF ligands (51). In another study, blockade of EGFR activity was shown to potentiate IGF1R signaling by enhancing the ability of IGF1R to couple to IRS1 (52). In models of lung cancer, increased IGF1R activation was shown to mediate chromatin modifications that confer a reversible state of "drug tolerance" to gefitinib (53).…”

Section: Discussionmentioning

confidence: 99%

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

Kjær

Lindsted

Fröhlich

et al. 2016

Molecular Cancer Therapeutics

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Squamous cell carcinomas (SCC) arising in upper parts of the aerodigestive tract are among the leading causes of death worldwide. EGFR has been found to play an essential role in driving the malignancy of SCC of the upper aerodigestive tract (SCCUAT), but, despite this, clinical results using a range of different EGFR-targeted agents have been disappointing. Cetuximab is currently the only EGFR-targeted agent approved by the FDA for treatment of SCCUAT. However, intrinsic and acquired cetuximab resistance is a major problem for effective therapy. Thus, a better understanding of the mechanisms responsible for cetuximab resistance is valuable for development of the next generation of antibody therapeutics. In order to better understand the underlying mechanisms of cetuximab resistance in SCCUAT, we established from cetuximab-sensitive models cell lines with acquired resistance to cetuximab by continuous selective pressure in vitro and in vivo. Our results show that resistant clones maintain partial dependency on EGFR and that receptor tyrosine kinase plasticity mediated by HER3 and IGF1R plays an essential role. A multitarget mAb mixture against EGFR, HER3, and IGF1R was able to overcome cetuximab resistance in vitro. To our surprise, these findings could be extended to include SCCUAT cell lines with intrinsic resistance to cetuximab, suggesting that the triad consisting of EGFR, HER3, and IGF1R plays a key role in SCCUAT. Our results thus provide a rationale for simultaneous targeting of EGFR, HER3, and IGF1R in SCCUAT. Mol Cancer Ther; 15(7); 1614-26. Ó2016 AACR.

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“…The H292 lung cancer cell line was utilized due to its high level of EGFR and IGF-IR expression and its in vitro sensitivity to growth inhibition by anti-EGFR agents. 30,31 H292 also responds to stimulation with EGF and IGF ligands by activating EGFR and IGF-IR and downstream pathways. The increased activity of EI-Tandem compared to the monospecific Adnectins might be, in part, due to the differences in the positioning of PEG end groups in these molecules resulting from steric hinderance for binding to the EGFR or …”

Section: O N O T D I S T R I B U T Ementioning

confidence: 99%

A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor

Emanuel

Engle

Chao

et al. 2011

mAbs

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Feedback Mechanisms Promote Cooperativity for Small Molecule Inhibitors of Epidermal and Insulin-Like Growth Factor Receptors

Abstract: Epidermal growth factor receptor (EGFR) and insulin-like growth factor

Cited by 182 publications

References 33 publications

Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

Insulin-Like Growth Factor-1 Receptor Inhibition Induces a Resistance Mechanism via the Epidermal Growth Factor Receptor/HER3/AKT Signaling Pathway: Rational Basis for Cotargeting Insulin-Like Growth Factor-1 Receptor and Epidermal Growth Factor Receptor in Hepatocellular Carcinoma

Cetuximab Resistance in Squamous Carcinomas of the Upper Aerodigestive Tract Is Driven by Receptor Tyrosine Kinase Plasticity: Potential for mAb Mixtures

A fibronectin scaffold approach to bispecific inhibitors of epidermal growth factor receptor and insulin-like growth factor-I receptor

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