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Insulin Receptor Isoforms in Cancer.

Veronica Vella1,2, Agostino Milluzzo3, Nunzio Massimo Scalisi4

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The insulin receptor (IR) isoform A is overexpressed in many cancers, promoting tumor growth and resistance to therapies. Targeting both insulin receptor and IGF-1 receptor may offer a new cancer treatment strategy.

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IGF-1RIGF-2cancerhybrid receptorsinsulininsulin receptorinsulin receptor isoformssplicing factors

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Area of Science:

  • Oncology
  • Molecular Biology
  • Endocrinology

Background:

  • The insulin receptor (IR) mediates metabolic and mitogenic effects.
  • IR is often overexpressed in obesity, diabetes, and various cancers, particularly as the IR-A isoform.
  • Cancer cells exhibit resistance in metabolic pathways, leading to compensatory hyperinsulinemia.

Purpose of the Study:

  • To investigate the role of insulin receptor (IR) isoform expression in cancer.
  • To understand the mechanisms regulating IR isoform predominance in tumors.
  • To explore the clinical implications of IR-A overexpression in cancer, including therapeutic resistance.

Main Methods:

  • Analysis of IR isoform expression in cancer tissues.
  • Investigation of molecular mechanisms regulating IR alternative splicing and expression.
  • Correlation of IR isoform levels with clinical outcomes and therapeutic responses.

Main Results:

  • IR is frequently overexpressed in cancers, predominantly as the IR-A isoform due to alternative splicing of exon 11.
  • Increased IR-A:IR-B ratio enhances cancer cell proliferation in response to insulin and locally produced IGF-2.
  • Dysregulation of mRNA transcription, splicing factors, non-coding RNAs, and protein degradation contribute to IR-A predominance.

Conclusions:

  • IR-A isoform overexpression in cancer is linked to increased stemness, tumor progression, and resistance to targeted therapies.
  • IR-A overexpression may serve as a predictive biomarker for resistance to IGF-1R targeted therapies.
  • Co-targeting IGF-1R and IR-A presents a promising therapeutic strategy for improving cancer treatment efficacy.