Combating Resistance to Anti-IGFR Antibody by Targeting the Integrin β 3-Src Pathway

Bidirectional signaling between TM4SF5 and IGF1R promotes resistance to EGFR kinase inhibitors

“…1A, left), in agreement with the previous report [18]. In the reverse experiment, we found that overexpression of IGF1R in SNU449 cells also enhanced TM4SF5 expression and its downstream signaling activities, including Akt and ERKs downstream of IGF1R [19] (Fig. 1A, right).…”

“…E746-A750) in exon 19 and an L858R substitution in exon 21, are significantly sensitive to the EGFR inhibitor gefitinib [1]. However, continued gefitinib therapy does not result in increased the survival of patients with the EGFR-sensitive mutations, due to acquired resistance caused by T790M substitution in the EGFR kinase domain of exon 20 [2].…”

IGF2 signaling and regulation in cancer

“…Trials of combination therapies (IGF1R antibody together with standard chemotherapy or compounds such as Sorafenib, Everolimus and Cetuximab) are actively recruiting (clinicaltrials.gov). The initial unfavorable results could be due to the fact that patients A c c e p t e d M a n u s c r i p t were not selected on their status of the IGF signaling pathway and that resistance to IGF1R inhibition is quickly acquired through compensatory signaling through the IR-A/B (60,61). For example, Ganitumab's effectiveness has been shown to correlate with IGF2 expression and PTEN mutational status.…”

Activation of insulin-like growth factor receptor signaling mediates resistance to histone deacetylase inhibitors

“…Immunohistochemical (IHC) analysis to detect pIGF-1R and proliferating cell nuclear antigen (PCNA) in tumors was performed as described previously [19]. To determine the level of apoptotic cell death in tumors, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) staining was performed using a commercially available kit (In Situ Cell Death Detection Kit, TMR red; Roche) and according to the manufacturer's instructions.…”