ArticleProceedings of the National Academy of Sciences of the United States of America2010
Insulin receptor functionally enhances multistage tumor progression and conveys intrinsic resistance to IGF-1R targeted therapy.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2010. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 141 papers.
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Who cites it
141 citing papers in PubMed, 234 citations in OpenAlex.
- Randomised Phase 2 study of maintenance linsitinib (OSI-906) in combination with erlotinib compared with placebo plus erlotinib after platinum-based chemotherapy in patients with advanced non-small cell lung cancer.British journal of cancer · 2017Trial
- Phase 2 Study of Erlotinib in Combination With Linsitinib (OSI-906) or Placebo in Chemotherapy-Naive Patients With Non-Small-Cell Lung Cancer and Activating Epidermal Growth Factor Receptor Mutations.Clinical lung cancer · 2017Trial
- Response of the insulin-like growth factor (IGF) system to IGF-IR inhibition and androgen deprivation in a neoadjuvant prostate cancer trial: effects of obesity and androgen deprivation.The Journal of clinical endocrinology and metabolism · 2013Trial
- Insulin receptor expression and its association with hyperinsulinemia in triple negative breast cancer.Journal of the Endocrine Society · 2026Article
- Obesity and Cancer: From Systemic Metabolic Reprogramming to Immunotherapy Paradox.Metabolites · 2026Review
- Correlation between insulin receptor expression and tumor cell proliferation, recurrence and metastasis in well-differentiated pancreatic neuroendocrine neoplasms.Endocrine connections · 2025Article
- Role and therapeutic potential of the NEDD4 family in breast cancer.Frontiers in pharmacology · 2025Review
- Sex-dimorphic tumor growth is regulated by tumor microenvironmental and systemic signals.Science advances · 2024Article
- Autocrine IGF-II-Associated Cancers: From a Rare Paraneoplastic Event to a Hallmark in Malignancy.Biomedicines · 2023Article
- Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance.International journal of molecular sciences · 2023Review
- Metabolic intervention by low carbohydrate diet suppresses the onset and progression of neuroendocrine tumors.Cell death & disease · 2023Article
- IGF2: A Role in Metastasis and Tumor Evasion from Immune Surveillance?Biomedicines · 2023Review
- Cell cycle control by the insulin-like growth factor signal: at the crossroad between cell growth and mitotic regulation.Cell cycle (Georgetown, Tex.) · 2023Review
- Multifaceted involvements of Paneth cells in various diseases within intestine and systemically.Frontiers in immunology · 2023Review
- Article
- Cixutumumab reveals a critical role for IGF-1 in adipose and hepatic tissue remodelling during the development of diet-induced obesity.Adipocyte · 2022Article
- N-Linked Glycosylation in Chinese Hamster Ovary Cells Is Critical for Insulin-like Growth Factor 1 Signaling.International journal of molecular sciences · 2022Article
- Grabody B, an IGF1 receptor-based shuttle, mediates efficient delivery of biologics across the blood-brain barrier.Cell reports methods · 2022Article
- Identification of Factors Driving Doxorubicin-Resistant Ewing Tumor Cells to Survival.Cancers · 2022Article
- Subventricular zone adult mouse neural stem cells require insulin receptor for self-renewal.Stem cell reports · 2022Article
81 more citing papers are in PubMed but not listed here.
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Authors and funding
4 authors at 3 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
The type 1 insulin-like growth factor receptor (IGF-1R) tyrosine kinase is an important mediator of the protumorigenic effects of IGF-I/II, and inhibitors of IGF-1R signaling are currently being tested in clinical cancer trials aiming to assess the utility of this receptor as a therapeutic target. Despite mounting evidence that the highly homologous insulin receptor (IR) can also convey protumorigenic signals, its direct role in cancer progression has not been genetically defined in vivo, and it remains unclear whether such a role for IR signaling could compromise the efficacy of selective IGF-1R targeting strategies. A transgenic mouse model of pancreatic neuroendocrine carcinogenesis engages the IGF signaling pathway, as revealed by its dependence on IGF-II and by accelerated malignant progression upon IGF-1R overexpression. Surprisingly, preclinical trials with an inhibitory monoclonal antibody to IGF-1R did not significantly impact tumor growth, prompting us to investigate the involvement of IR. The levels of IR were found to be significantly up-regulated during multistep progression from hyperplastic lesions to islet tumors. Its functional involvement was revealed by genetic disruption of the IR gene in the oncogene-expressing pancreatic beta cells, which resulted in reduced tumor burden accompanied by increased apoptosis. Notably, the IR knockout tumors now exhibited sensitivity to anti-IGF-1R therapy; similarly, high IR to IGF-1R ratios demonstrably conveyed resistance to IGF-1R inhibition in human breast cancer cells. The results predict that elevated IR signaling before and after treatment will respectively manifest intrinsic and adaptive resistance to anti-IGF-1R therapies.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.