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IGF1R

Friday 7 January 2005

Pathology

- germline mutations in resistance to IGF1 (intrauterine growth retardation and subsequent short stature)

- IGF1R overexpression by 15q25-26 amplification in tumors

- IGF1R overexpression without 15q25-26 amplicon amplification

  • pediatric gastrointestinal stromal tumors (pediatric GIST) (20162573)

- Increased copy number at chromosome 15q26.3

- Expression levels of the ret proto-oncogene (RET), insulin-like growth factor 1 receptor (IGFR1), and insulin-like growth factor 2 (IFG2) correlate with poor metastasis-free survival, supporting a role for ERK/MAPK and PI3K/AKT pathways in clinically aggressive myxoid liposarcomas. (19368956)

- Autocrine IGF-1/IGF-1R signalling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia. (20007139)

- Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification. (20162573)

- Consistent lack of IGF1R expression in intestinal GISTs. (22892600)

  • It should be considered an additional immunohistochemical marker in the differential diagnosis between GISTs and non-GIST sarcomas. (22892600)
  • Because inhibition of IGF1R signaling might become a therapeutic target in GISTs, screening for IGF1R expression may become important in the near future. (22892600)

Targeted therapy

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.

The cooperation between epidermal growth factor receptor (EGFR) and IGF-IR could cause resistance to inhibitors of individual receptor tyrosine kinases.

For example, 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. (Mol Cancer Ther; 10(12); 2437–48, 2011)

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. 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. (Mol Cancer Ther; 10(12); 2437–48, 2011)

See also

- IGF signaling pathway

References

- Expression of the Receptor for Type I Insulin-like Growth Factor (IGF1R) in Gastrointestinal Stromal Tumors: An Immunohistochemical Study of 1078 Cases With Diagnostic and Therapeutic Implications. Lasota J, Wang Z, Kim SY, Helman L, Miettinen M. Am J Surg Pathol. 2012 Aug 13. PMID: 22892600

- Strong expression of IGF1R in pediatric gastrointestinal stromal tumors without IGF1R genomic amplification. Janeway KA, Zhu MJ, Barretina J, Perez-Atayde A, Demetri GD, Fletcher JA. Int J Cancer. 2010 Feb 16. PMID: 20162573

- Oncogenic BRAF mutation with CDKN2A inactivation is characteristic of a subset of pediatric malignant astrocytomas. Schiffman JD, Hodgson JG, VandenBerg SR, Flaherty P, Polley MY, Yu M, Fisher PG, Rowitch DH, Ford JM, Berger MS, Ji H, Gutmann DH, James CD. Cancer Res. 2010 Jan 15;70(2):512-9. PMID: 20068183

- Autocrine IGF-1/IGF-1R signalling is responsible for constitutive PI3K/Akt activation in acute myeloid leukemia: therapeutic value of neutralizing anti-IGF-1R antibody. Chapuis N, Tamburini J, Cornillet-Lefebvre P, Gillot L, Bardet V, Willems L, Park S, Green AS, Ifrah N, Dreyfus F, Mayeux P, Lacombe C, Bouscary D. Haematologica. PMID: 20007139

- Natrajan R, Reis-Filho JS, Little SE, Messahel B, Brundler MA, Dome JS, Grundy PE, Vujanic GM, Pritchard-Jones K, Jones C. Blastemal expression of type I insulin-like growth factor receptor in Wilms’ tumors is driven by increased copy number and correlates with relapse. Cancer Res. 2006 Dec 1;66(23):11148-55. PMID: 17145858