Evaluation of IGF1R and phosphorylated IGF1R as targets in HER2-positive breast cancer cell lines and tumours
- 1k Downloads
Insulin-like growth factor-1 receptor (IGF1R) signalling is implicated in resistance to trastuzumab. However, the benefit of co-targeting HER2 and IGF1R has not been extensively studied, and the relationship between activated IGF1R and clinical response to trastuzumab has not been reported. This study aimed to evaluate the combination of trastuzumab with IGF1R tyrosine kinase inhibitors (TKIs) in a panel of HER2-positive breast cancer cell lines, and to examine the relationship between IGF1R expression and activation and response to trastuzumab in HER2-positive breast cancer patients. The anti-proliferative effects of trastuzumab combined with IGF1R TKIs BMS-536924 or NVP-AEW541 were measured in nine HER2-positive cell lines. IGF1R and phosphorylated IGF1R/insulin receptor (pIGF1R/IR) were measured by immunohistochemistry in 160 tumour samples from trastuzumab-treated patients (ICORG 06-22). The HER2-positive cell lines displayed varying sensitivity to IGF1R TKIs alone (IC50s: 0.7 to >10 μM). However, when combined with trastuzumab, a significantly enhanced effect was observed in five cell lines treated with BMS-536924, and three with NVP-AEW541. While IGF1R levels correlated with reduced response to NVP-AEW541 alone, neither IGF1R nor pIGF1R were predictive of response to BMS-536924 or NVP-AEW541 in combination with trastuzumab. Low HER2 levels correlated with response to BMS-536924 in combination with trastuzumab. Akt levels correlated with improved response to trastuzumab and NVP-AEW541 (P = 0.039). Cytoplasmic IGF1R staining was observed in all tumours, membrane IGF1R was detected in 13.8 %, and pIGF1R/IR was detected in 48.8 %. Although membrane IGF1R staining was associated with larger tumour size (P = 0.041), and lower tumour grade (P = 0.024), no association between IGF1R or pIGF1R/IR and patient survival was observed. In conclusion, while neither IGF1R expression nor activation was predictive of response to trastuzumab, these pre-clinical data provide evidence that co-targeting HER2 and IGF1R may be beneficial in some HER2-amplified breast cancers.
KeywordsHER2 Insulin-like growth factor-1 receptor IGF1R Trastuzumab Resistance Breast cancer
We would like to acknowledge ICORG, the All Ireland Cooperative Oncology Research Group who has sponsored the study (Study no. 06-22). We thank Deirdre McMahon of St. Vincent’s University Hospital for help with TMA processing. This study was supported by the Health Research Board (HRB), Science Foundation Ireland (SFI) and the Cancer Clinical Research Trust (CCRT).
Conflict of interest
John Crown has received research support and speaker’s honoraria from Roche.
- 4.Cobleigh MA, Vogel CL, Tripathy D, Robert NJ, Scholl S, Fehrenbacher L, Wolter JM, Paton V, Shak S, Lieberman G, Slamon DJ (1999) Multinational study of the efficacy and safety of humanized anti-HER2 monoclonal antibody in women who have HER2-overexpressing metastatic breast cancer that has progressed after chemotherapy for metastatic disease. J Clin Oncol 17(9):2639–2648PubMedGoogle Scholar
- 5.Slamon DJ, Leyland-Jones B, Shak S, Fuchs H, Paton V, Bajamonde A, Fleming T, Eiermann W, Wolter J, Pegram M, Baselga J, Norton L (2001) Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344(11):783–792PubMedCrossRefGoogle Scholar
- 8.Press MF, Finn RS, Cameron D, Di Leo A, Geyer CE, Villalobos IE, Santiago A, Guzman R, Gasparyan A, Ma Y, Danenberg K, Martin AM, Williams L, Oliva C, Stein S, Gagnon R, Arbushites M, Koehler MT (2008) HER-2 gene amplification, HER-2 and epidermal growth factor receptor mRNA and protein expression, and lapatinib efficacy in women with metastatic breast cancer. Clin Cancer Res 14(23):7861–7870PubMedCrossRefGoogle Scholar
- 12.Nielsen TO, Andrews HN, Cheang M, Kucab JE, Hsu FD, Ragaz J, Gilks CB, Makretsov N, Bajdik CD, Brookes C, Neckers LM, Evdokimova V, Huntsman DG, Dunn SE (2004) Expression of the insulin-like growth factor I receptor and urokinase plasminogen activator in breast cancer is associated with poor survival: potential for intervention with 17-allylamino geldanamycin. Cancer Res 64(1):286–291PubMedCrossRefGoogle Scholar
- 14.Jerome L, Alami N, Belanger S, Page V, Yu Q, Paterson J, Shiry L, Pegram M, Leyland-Jones B (2006) Recombinant human insulin-like growth factor binding protein 3 inhibits growth of human epidermal growth factor receptor-2-overexpressing breast tumors and potentiates herceptin activity in vivo. Cancer Res 66(14):7245–7252PubMedCrossRefGoogle Scholar
- 19.Kostler WJ, Hudelist G, Rabitsch W, Czerwenka K, Muller R, Singer CF, Zielinski CC (2006) Insulin-like growth factor-1 receptor (IGF-1R) expression does not predict for resistance to trastuzumab-based treatment in patients with Her-2/neu overexpressing metastatic breast cancer. J Cancer Res Clin Oncol 132(1):9–18PubMedCrossRefGoogle Scholar
- 20.Shimizu C, Hasegawa T, Ando M, Fujiwara Y, Tani Y (2004) Relation between Insulin-like growth factor-1 receptor (IGF-1R) expression and the efficacy of trastuzumab (T) monotherapy for hormone-resistant HER2-postitive metastatic breast cancer (MBC). J Clin Oncol 22(14):9578Google Scholar
- 22.Harris LN, You F, Schnitt SJ, Witkiewicz A, Lu X, Sgroi D, Ryan PD, Come SE, Burstein HJ, Lesnikoski BA, Kamma M, Friedman PN, Gelman R, Iglehart JD, Winer EP (2007) Predictors of resistance to preoperative trastuzumab and vinorelbine for HER2-positive early breast cancer. Clin Cancer Res 13(4):1198–1207PubMedCrossRefGoogle Scholar
- 24.Reinholz MM, Dueck AC, Chen B, Geiger X, McCullough AE, Jenkins RB, Lingle WL, Andorfer C, Davidson NE, Martino S, Kaufman PA, Kutteh LA, Sledge GW, Harris LN, Gralow J, Perez EA (2011) Effect of IGF1R protein expression on benefit to adjuvant trastuzumab in early-stage HER2 + breast cancer in NCCTG N9831 trial. J Clin Oncol 29 (suppl):abstr 10503Google Scholar
- 25.Law JH, Habibi G, Hu K, Masoudi H, Wang MY, Stratford AL, Park E, Gee JM, Finlay P, Jones HE, Nicholson RI, Carboni J, Gottardis M, Pollak M, Dunn SE (2008) Phosphorylated insulin-like growth factor-i/insulin receptor is present in all breast cancer subtypes and is related to poor survival. Cancer Res 68(24):10238–10246PubMedCrossRefGoogle Scholar
- 28.Bielen A, Box G, Perryman L, Bjerke L, Popov S, Jamin Y, Jury A, Valenti M, Brandon Ade H, Martins V, Romanet V, Jeay S, Raynaud FI, Hofmann F, Robinson SP, Eccles SA, Jones C (2012) Dependence of Wilms tumor cells on signaling through insulin-like growth factor 1 in an orthotopic xenograft model targetable by specific receptor inhibition. Proc Natl Acad Sci USA 109(20):E1267–E1276PubMedCrossRefGoogle Scholar
- 29.Wittman M, Carboni J, Attar R, Balasubramanian B, Balimane P, Brassil P, Beaulieu F, Chang C, Clarke W, Dell J, Eummer J, Frennesson D, Gottardis M, Greer A, Hansel S, Hurlburt W, Jacobson B, Krishnananthan S, Lee FY, Li A, Lin TA, Liu P, Ouellet C, Sang X, Saulnier MG, Stoffan K, Sun Y, Velaparthi U, Wong H, Yang Z, Zimmermann K, Zoeckler M, Vyas D (2005) Discovery of a (1H-benzoimidazol-2-yl)-1H-pyridin-2-one (BMS-536924) inhibitor of insulin-like growth factor I receptor kinase with in vivo antitumor activity. J Med Chem 48(18):5639–5643PubMedCrossRefGoogle Scholar
- 34.Ueda S, Tsuda H, Sato K, Takeuchi H, Shigekawa T, Matsubara O, Hiraide H, Mochizuki H (2006) Alternative tyrosine phosphorylation of signaling kinases according to hormone receptor status in breast cancer overexpressing the insulin-like growth factor receptor type 1. Cancer Sci 97(7):597–604PubMedCrossRefGoogle Scholar
- 35.Hartog H, Horlings HM, van der Vegt B, Kreike B, Ajouaou A, van de Vijver MJ, Marike Boezen H, de Bock GH, van der Graaf WT, Wesseling J (2011) Divergent effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple negative invasive ductal breast carcinoma. Breast Cancer Res Treat 129(3):725–736PubMedCrossRefGoogle Scholar
- 38.Wallborn T, Wuller S, Klammt J, Kruis T, Kratzsch J, Schmidt G, Schlicke M, Muller E, van de Leur HS, Kiess W, Pfaffle R (2010) A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation. J Clin Endocrinol Metab 95(5):2316–2324PubMedCrossRefGoogle Scholar