Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation

Gong, Yuanying; Ma, Yufang; Sinyuk, Maksim; Loganathan, Sudan N.; Thompson, Reid C.; Sarkaria, Jann N.; Chen, Wenbiao; Lathia, Justin D.; Mobley, Bret; Clark, Stephen W.; Wang, Jialiang

doi:10.1093/neuonc/nov096

Cited by 73 publications

(76 citation statements)

References 46 publications

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“…GBM46 was not affected by insulin or IGF1 (Fig. 1C), which was consistent with our recent findings that GBM46 did not express InsR or IGF1R (13). These results indicate that activation of the InsR/IGF1R pathway represents an important mechanism in resistance to EGFR inhibitors in glioblastoma.…”

Section: Resultssupporting

confidence: 92%

“…Specifically, active InsR and/or IGF1R were identified in 9 out of 14 primary glioblastoma specimens. Our group recently demonstrated expression of InsR and IGF1R in glioblastoma surgical specimens and PDX lines (13). Both receptors were implicated in AKT regulation, as knocking down either one of them reduced AKT activity (13).…”

Section: Discussionmentioning

confidence: 99%

“…Our group recently demonstrated expression of InsR and IGF1R in glioblastoma surgical specimens and PDX lines (13). Both receptors were implicated in AKT regulation, as knocking down either one of them reduced AKT activity (13). In the current study, we demonstrated that activation of the InsR/IGF1R pathway conferred resistance to EGFR inhibitors in the majority of glioblastoma tumors affected by EGFR aberration.…”

Section: Discussionmentioning

confidence: 99%

“…Non-genetic mechanisms may also contribute to compensatory activation of additional RTKs. Our group recently demonstrated that insulin receptor (InsR) and the closely related family member insulin-like growth factor 1 receptor (IGF1R) are frequently activated in glioblastoma (13). Both InsR and IGF1R are rarely mutated or amplified in glioblastoma.…”

Section: Introductionmentioning

confidence: 99%

“…Rather, activation of the InsR/IGF1R pathway appears to be primarily mediated through ligands produced via endocrine mechanisms. Genetic or pharmacological targeting of InsR or IGF1R has significant impact on AKT signaling in glioblastoma (13), suggesting potential implications in resistance to EGFR inhibitors. Exactly which RTK pathway(s) play significant roles in glioblastoma resistance to EGFR inhibitors remains an open question.…”

Section: Introductionmentioning

confidence: 99%

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InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma

Tang

Thompson

et al. 2016

Clinical Cancer Research

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Purpose Aberrant activation of epidermal growth factor receptor (EGFR) is a hallmark of glioblastoma. However, EGFR inhibitors exhibit at best modest efficacy in glioblastoma. This is in sharp contrast to the observations in EGFR-mutant lung cancer. We examined whether activation of functionally redundant receptor tyrosine kinases (RTKs) conferred resistance to EGFR inhibitors in glioblastoma. Experimental Design We collected a panel of patient-derived glioblastoma xenograft (PDX) lines that maintained expression of wild type or mutant EGFR in serial xenotransplantation and tissue cultures. Using this physiologically relevant platform, we tested the abilities of several RTK ligands to protect glioblastoma cells against an EGFR inhibitor, gefitinib. Based on the screening results, we further developed a combination therapy co-targeting EGFR and insulin receptor (InsR)/insulin-like growth factor 1 receptor (IGF1R). Results Insulin and IGF1 induced significant protection against gefitinib in the majority of EGFR-dependent PDX lines with one exception that did not expression InsR or IGF1R. Blockade of the InsR/IGF1R pathway synergistically improved sensitivity to gefitinib or dacomitinib. Gefitinib alone effectively attenuated EGFR activities and the downstream MEK/ERK pathway. However, repression of AKT and induction of apoptosis required concurrent inhibition of both EGFR and InsR/IGF1R. A combination of gefitinib and OSI-906, a dual InsR/IGF1R inhibitor, was more effective than either agent alone to treat subcutaneous glioblastoma xenograft tumors. Conclusions Our results suggest that activation of the InsR/IGF1R pathway confers resistance to EGFR inhibitors in EGFR-dependent glioblastoma through AKT regulation. Concurrent blockade of these two pathways holds promise to treat EGFR-dependent glioblastoma.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma

Tang

Thompson

et al. 2016

Clinical Cancer Research

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From Hyperinsulinemia to Cancer Progression: How Diminishing Glucose Storage Capacity Fuels Insulin Resistance

Kareva

2024

Aging and Cancer

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BackgroundType 2 diabetes (T2D) is a complex metabolic disorder characterized by insulin resistance, hyperglycemia, and hyperinsulinemia. A significant portion of individuals with T2D are unaware of their condition until it has reached advanced stages. T2D is also associated with an increased risk and worse prognosis of cardiovascular disease, cognitive decline, and cancer. Understanding the mechanisms underlying the emergence of insulin resistance is critical for improving early detection and therapeutic interventions.MethodsAn updated framework is proposed to describe the emergence of insulin resistance that precedes the development of T2D. The model focuses on the impact of diminishing capacity to store excess glucose, which can occur due to a multitude of factors, including age‐related muscle loss. The model is used to simulate responses to oral glucose tolerance tests (OGTTs) to capture the transition from a normal to a diabetic phenotype, as defined by the Kraft criteria. Additionally, the model is used to explore how the metabolic environment influences tumor progression, drawing on experimental data regarding the impact of transient diabetic phenotypes and hyperinsulinemia on cancer therapy efficacy.ResultsThe model successfully demonstrates that reduced glucose storage capacity can qualitatively reproduce the progression from normal to diabetic phenotypes observed in OGTT responses. Furthermore, it shows that tumor progression or regression is highly dependent on the host's metabolic environment, particularly hyperinsulinemia. This aligns with experimental results that connect drug‐induced hyperinsulinemia to a loss of therapeutic efficacy against tumors, whereas the reversal of the diabetic phenotype could restore drug sensitivity and treatment response.ConclusionsThis study highlights the critical role of hyperinsulinemia, even in normoglycemic individuals, in both the progression of T2D and the modulation of cancer therapy outcomes. Addressing hyperinsulinemia emerges as a promising strategy to enhance cancer treatment efficacy and improve overall health outcomes in patients with or at risk for T2D.

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Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting

Tian

Kang

et al. 2020

Advanced Science

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Glioblastoma is the most malignant cancer in the brain and currently incurable. It is urgent to identify effective targets for this lethal disease. Inhibition of such targets should suppress the growth of cancer cells and, ideally also precancerous cells for early prevention, but minimally affect their normal counterparts. Using genetic mouse models with neural stem cells (NSCs) or oligodendrocyte precursor cells (OPCs) as the cells‐of‐origin/mutation, it is shown that the susceptibility of cells within the development hierarchy of glioma to the knockout of insulin‐like growth factor I receptor (IGF1R) is determined not only by their oncogenic states, but also by their cell identities/states. Knockout of IGF1R selectively disrupts the growth of mutant and transformed, but not normal OPCs, or NSCs. The desirable outcome of IGF1R knockout on cell growth requires the mutant cells to commit to the OPC identity regardless of its development hierarchical status. At the molecular level, oncogenic mutations reprogram the cellular network of OPCs and force them to depend more on IGF1R for their growth. A new‐generation brain‐penetrable, orally available IGF1R inhibitor harnessing tumor OPCs in the brain is also developed. The findings reveal the cellular window of IGF1R targeting and establish IGF1R as an effective target for the prevention and treatment of glioblastoma.

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Insulin-mediated signaling promotes proliferation and survival of glioblastoma through Akt activation

Abstract: Taken together, our work suggests that glioblastoma is sensitive to the mitogenic functions of insulin, thus significant insulin exposure imposes risks to glioblastoma patients. Additionally, dual inhibition of InsR and IGF1R exhibits promise for treating glioblastoma.

Cited by 73 publications

References 46 publications

InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma

InsR/IGF1R Pathway Mediates Resistance to EGFR Inhibitors in Glioblastoma

From Hyperinsulinemia to Cancer Progression: How Diminishing Glucose Storage Capacity Fuels Insulin Resistance

Oncogenic State and Cell Identity Combinatorially Dictate the Susceptibility of Cells within Glioma Development Hierarchy to IGF1R Targeting

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