IGF‐1R pathway activation as putative biomarker for linsitinib therapy to revert tamoxifen resistance in ER‐positive breast cancer

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.

In Silico Molecular Dynamics Docking of Drugs to the Inhibitory Active Site of SARS-CoV-2 Protease and Their Predicted Toxicology and ADME

“…Tucatinib (Rank 11, BE=-9, B11652) is indicated for HER-2 positive metastatic breast cancer [68] . Linsitinib (Rank 12, BE=-9, B06075) was investigated for GI stromal, adrenocortical, breast, and prostate cancers [69][70][71][72] . Figure 3 illustrates the 2D molecular structure of the top 20 experimental drugs; the top 10 are described below with citations.…”

Growth Hormone/Insulin Growth Factor Axis in Sex Steroid Associated Disorders and Related Cancers

“…It has been reported that increased IGF-1R activity in cancers may occur secondary to the loss of tumour suppressor genes such as TP53, BRCA1 , von-Hippel Lindau protein and Wilms’ tumour-1 ( Werner, 2012 ). Kruger et al, also reported that IGF-1R activation rather than IGF-1R overexpression is sufficient to induce downstream activation of the MAPK/PI3K signalling pathways and overcome tamoxifen treatment in breast cancer ( Kruger et al, 2020 ).…”

“…One of the mechanisms involved in the crosstalk between the ER and the IGF-1R involves E 2 induced phosphorylation of the IGF-1R and subsequent activation of ERK ( Kahlert et al, 2000 ). Phosphorylation of IGF-1R and subsequent activation of downstream signalling cascades were also found to contribute to tamoxifen resistance and drive cell proliferation in breast cancer ( Kruger et al, 2020 ). The IGF-1/IGF-1R axis can also induce phosphorylation of ER through ribosomal S6 kinase 1 (S6K1), downstream of the PI3K/AKT/mTOR pathway which results in the upregulation of IGF-1, IGF-1R and other ER target genes ( Becker et al, 2011 ).…”

“…Interestingly, they also report that in cell lines, stimulation rather than overexpression of IGF-1R is driving tamoxifen resistance to be abrogated by linsitinib. This highlights the need for biomarkers that indicate activity of the IGF signalling pathway ( Kruger et al, 2020 ).…”

Insights into Growth Factors in Liver Carcinogenesis and Regeneration: An Ongoing Debate on Minimizing Cancer Recurrence after Liver Resection

“…Inhibitor of IGF-1 [125] Inhibitors of IGF-1 [126][127][128][129] Abbreviations: c-MET, mesenchymal-epithelial transition factor; DKK1, Dickkopf-1EGF; epidermal growth factor; EGFR, Epidermal growth factor receptor; EMT, Epithelial-mesenchymal transition; HCC, hepatocarcinoma; HGF, Hepatocyte growth factor; HMGA2, High-mobility group protein A2; IGF-1, Insulin-like growth factor; PD-L1, Programmed death-ligand 1; ROS, Reactive oxygen species.…”