Sir,
We read with great interest the Letter to the Editor from Shimokawa et al (2011) that reported significant associations between the expressions of the insulin-like growth factor type I receptor (IGF-IR) and those of E-cadherin and γ-catenin in non-small cell lung cancer (NSCLC) biopsies (Shimokawa et al, 2011). These data reproduce previous observations from our group. We have also observed a correlation between the expressions of IGF-IR and E-cadherin, particularly in NSCLC tumours with a high degree of differentiation (Gualberto et al, 2010). Furthermore, using unsupervised Bayesian clustering of epithelial-to-mesenchymal transition (EMT)- and IGF-IR-related markers, we identified three NSCLC subsets that resembled the steps of the EMT and we named epithelial-like, transitional-like and mesenchymal-like (Gualberto et al, 2010). Several markers of the IGF-IR pathway such as nuclear insulin receptor substrate-1 were overexpressed in the transitional subset and a higher objective response rate to the combination of chemotherapy and the anti-IGF-IR antibody figitumumab was observed in patients with transitional tumours (Gualberto et al, 2010). Thus, we agree with Shimokawa et al (2011) that analysis of tumour EMT status may contribute to a better understanding of the sensitivity to anti-IGF-IR therapy.
Shimokawa et al (2011) also pointed out that we have reported an inverse correlation in NSCLC patients between serum IGF-1 and tumour E-cadherin levels (Gualberto et al, 2011). We speculate that the fact that tumour E-cadherin is directly correlated with tumour IGF-IR and inversely correlated with serum IGF-1 may indicate differential functions for the non-activated (low or no ligand) vs the activated (in the presence of IGFs) IGF-1 receptor. Evidence supports the involvement of the IGF-IR in both differentiation and cellular growth and metastasis, with engagement of the receptor by IGFs-inducing neo-expression of mesenchymal markers, E-cadherin downregulation and cell migration (reviewed in Julien-Grille et al, 2005). These observations may have therapeutic implications. Of note, our key finding that high serum (free) IGF-1 levels may identify a subset of NSCLC patients who preferentially benefit from anti-IGF-IR therapy has now been independently corroborated by other groups (Goto et al, 2011; Ramalingam et al, 2011).
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29 March 2012
This paper was modified 12 months after initial publication to switch to Creative Commons licence terms, as noted at publication
References
Goto Y, Sekine I, Tanioka M, Shibata T, Tanai C, Asahina H, Nokihara H, Yamamoto N, Kunitoh H, Ohe Y, Kikkawa H, Ohki E, Tamura T (2011) Figitumumab combined with carboplatin and paclitaxel in treatment-naïve Japanese patients with advanced non-small cell lung cancer. Invest New Drugs; e-pub ahead of print 13 July 2011
Gualberto A, Dolled-Filhart M, Gustavson M, Christiansen J, Wang YF, Hixon ML, Reynolds J, McDonald S, Ang A, Rimm DL, Langer CJ, Blakely J, Garland L, Paz-Ares LG, Karp DD, Lee AV (2010) Molecular analysis of non-small cell lung cancer identifies subsets with different sensitivity to insulin-like growth factor I receptor inhibition. Clin Cancer Res 15: 4654–4665
Gualberto A, Hixon ML, Karp DD, Li D, Green S, Dolled-Filhart M, Paz-Ares LG, Novello S, Blakely J, Langer CJ, Pollak MN (2011) Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab. Br J Cancer 104: 68–74
Julien-Grille S, Moore R, Denat L, Morali OG, Delmas V, Bellacosa A, Larue L (2005) The role of insulin-like growth factors in the epithelial to mesenchymal transition. In: Savagner P (ed). Rise and fall of the epithelial phenotype: Concepts of epithelial-mesenchymal transition. Landes Bioscience: Montpellier, 215–235
Ramalingam SS, Spigel DR, Steins M, Engelman JA, Schneider C, Novello S, Eberhardt WE, Crino L, Janne PA, Liu L, Brownstein CM, Reck M (2011) Randomized, double-blind, phase II study of erlotinib in combination with placebo or R1507, a monoclonal antibody to insulin-like growth factor receptor-1 (IGF-1R), for advanced-stage non-small cell lung cancer (NSCLC). J Clin Oncol 29: 2011 (suppl; abstract 7527)
Shimokawa H, Uramoto H, Tanaka F (2011) Comment on ‘Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab’. Br J Cancer 105: 1465–1466
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M Hixon and M Pollak received research funds from Pfizer Inc. A Gualberto is a former employee of Pfizer Inc.
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Gualberto, A., Hixon, M. & Pollak, M. Reply: ‘Pre-treatment levels of circulating free IGF-1 identify NSCLC patients who derive clinical benefit from figitumumab’. Br J Cancer 105, 1467 (2011). https://doi.org/10.1038/bjc.2011.413
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DOI: https://doi.org/10.1038/bjc.2011.413