1. IGF-1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER-positive breast cancer.
- Author
-
Kruger DT, Alexi X, Opdam M, Schuurman K, Voorwerk L, Sanders J, van der Noort V, Boven E, Zwart W, and Linn SC
- Subjects
- Aged, Biomarkers, Tumor metabolism, Breast Neoplasms pathology, Cell Line, Tumor, Drug Resistance, Neoplasm, Drug Synergism, Female, Humans, Imidazoles administration & dosage, Immunohistochemistry, MAP Kinase Signaling System, MCF-7 Cells, Middle Aged, Neoplasm Staging, Phosphatidylinositol 3-Kinases metabolism, Phosphorylation, Pyrazines administration & dosage, Receptor, IGF Type 1 antagonists & inhibitors, Tamoxifen administration & dosage, Antineoplastic Combined Chemotherapy Protocols pharmacology, Breast Neoplasms drug therapy, Breast Neoplasms metabolism, Imidazoles pharmacology, Pyrazines pharmacology, Receptor, IGF Type 1 metabolism, Receptors, Estrogen metabolism, Tamoxifen pharmacology
- Abstract
Preclinical studies indicate that activated IGF-1R can drive endocrine resistance in ER-positive (ER+) breast cancer, but its clinical relevance is unknown. We studied the effect of IGF-1R signaling on tamoxifen benefit in patients and we searched for approaches to overcome IGF-1R-mediated tamoxifen failure in cell lines. Primary tumor blocks from postmenopausal ER+ breast cancer patients randomized between adjuvant tamoxifen versus nil were recollected. Immunohistochemistry for IGF-1R, p-IGF-1R/InsR, p-ERα(Ser118), p-ERα(Ser167) and PI3K/MAPK pathway proteins was performed. Multivariate Cox models were employed to assess tamoxifen efficacy. The association between p-IGF-1R/InsR and PI3K/MAPK pathway activation in MCF-7 and T47D cells was analyzed with Western blots. Cell proliferation experiments were performed under various growth-stimulating and -inhibiting conditions. Patients with ER+, IGF-1R-positive breast cancer without p-IGF-1R/InsR staining (n = 242) had tamoxifen benefit (HR 0.41, p = 0.0038), while the results for p-IGF-1R/InsR-positive patients (n = 125) were not significant (HR 0.95, p = 0.3). High p-ERα(Ser118) or p-ERα(Ser167) expression was associated with less tamoxifen benefit. In MCF-7 cells, IGF-1R stimulation increased phosphorylation of PI3K/MAPK proteins and ERα(Ser167) regardless of IGF-1R overexpression. This could be abrogated by the dual IGF-1R/InsR inhibitor linsitinib, but not by the IGF-IR-selective antibody 1H7. In MCF-7 and T47D cells, stimulation of the IGF-1R/InsR pathway resulted in cell proliferation regardless of tamoxifen. Abrogation of cell growth was regained by addition of linsitinib. In conclusion, p-IGF-1R/InsR positivity in ER+ breast cancer is associated with reduced benefit from adjuvant tamoxifen in postmenopausal patients. In cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib., (© 2019 The Authors. International Journal of Cancer published by John Wiley & Sons Ltd on behalf of UICC.)
- Published
- 2020
- Full Text
- View/download PDF