Oncogenic fusion proteins adopt the insulin-like growth factor signaling pathway

Abstract

The insulin-like growth factor-1 receptor (IGF1R) has been identified as a potent anti-apoptotic, pro-survival tyrosine kinase-containing receptor. Overexpression of the IGF1R gene constitutes a typical feature of most human cancers. Consistent with these biological roles, cells expressing high levels of IGF1R are expected not to die, a quintessential feature of cancer cells. Tumor specific chromosomal translocations that disrupt the architecture of transcription factors are a common theme in carcinogenesis. Increasing evidence gathered over the past fifteen years demonstrate that this type of genomic rearrangements is common not only among pediatric and hematological malignancies, as classically thought, but may also provide a molecular and cytogenetic foundation for an ever-increasing portion of adult epithelial tumors. In this review article we provide evidence that the mechanism of action of oncogenic fusion proteins associated with both pediatric and adult malignancies involves transactivation of the IGF1R gene, with ensuing increases in IGF1R levels and ligand-mediated receptor phosphorylation. Disrupted transcription factors adopt the IGF1R signaling pathway and elicit their oncogenic activities via activation of this critical regulatory network. Combined targeting of oncogenic fusion proteins along with the IGF1R may constitute a promising therapeutic approach.

Intermingling of chromosome territories

“…The closeness of certain pairs of gene loci in the nucleus has been found to be positively correlated with their probability of translocations . Numerous disease‐specific chromosomal rearrangements have been linked to different tumor types, constituting the foundation for current molecular diagnostics and treatment . The Philadelphia chromosome discovered by Hungerford and Nowell in 1959 has become a canonical example of such rearrangements.…”

“…2,43 Numerous disease-specific chromosomal rearrangements have been linked to different tumor types, constituting the foundation for current molecular diagnostics and treatment. [44][45][46] The Philadelphia chromosome discovered by Hungerford and Nowell in 1959 has become a canonical example of such rearrangements. The mechanism identified almost 15 years later is based on a translocation between chromosome 9 and 22 resulting in BCR/ABL1 fusion gene formation which is responsible for chronic myeloid leukemia, and thus it serves as a target for immunotherapy.…”

IGF2/IGF1R Signaling as a Therapeutic Target in MYB-Positive Adenoid Cystic Carcinomas and Other Fusion Gene-Driven Tumors

“…Studies in recent decades have shown that several oncogenic gene fusions interact with insulin-like growth factor (IGF) signaling at different levels [14,15]. IGF signaling is an ancient evolutionary conserved mechanism that regulates critical cellular processes such as cell proliferation and survival [16].…”

Genomics and Therapeutic Vulnerabilities of Primary Bone Tumors

“…Tumorigenesis in translocation-driven tumors is critically mediated via the IGF-1R signaling pathway [117]. Preclinical models of Ewing sarcomas show an autocrine activation of the IGF-1R-mediated signaling pathway [118], which promotes cell viability and drug escape [119,120].…”