Minireview: Were the IGF Signaling Inhibitors All Bad?

Beckwith, Heather; Yee, Douglas

doi:10.1210/me.2015-1157

Cited by 80 publications

(71 citation statements)

References 68 publications

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“…The authors further indicated that IGFIR mRNA extend to be more highly expressed in Luminal A and B subtypes compared with the basal-like and HER2-positive subtypes (173). Many IGFIR inhibitors (mAbs and TKIs) and IGF1/IGF2 neutralizing mABs have been developed and evaluated in clinical trials with some success in early trials but have failed to show benefits in larger phase III trials (174). Exploring predictive biomarkers may identify subpopulation of patients who may benefit from IGFIR inhibitors.…”

Section: 3 Other Rtksmentioning

confidence: 99%

The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer

Hsu

Hung

2016

Cancer Metastasis Rev

293

185

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Breast cancer affects approximately 1 in 8 women, and it is estimated that over 246,660 women in the United States will be diagnosed with breast cancer in 2016. Breast cancer mortality has decline over the last two decades due to early detection and improved treatment. Over the last few years, there is mounting evidence to demonstrate the prominent role of receptor tyrosine kinases (RTKs) in tumor initiation and progression, and targeted therapies against the RTKs have been developed, evaluated in clinical trials, and approved for many cancer types, including breast cancer. However, not all breast cancers are the same as evidenced by the multiple subtypes of the disease, with some more aggressive than others, showing differential treatment response to different types of drugs. Moreover, in addition to canonical signaling from the cell surface, many RTKs can be trafficked to various subcellular compartments, such as the multivesicular body and nucleus, where they carry out critical cellular functions, such as cell proliferation, DNA replication and repair, and therapeutic resistance. In this review, we provide a brief summary on the role of a selected number of RTKs in breast cancer and describe some mechanisms of resistance.

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Section: 3 Other Rtksmentioning

confidence: 99%

The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer

Hsu

Hung

2016

Cancer Metastasis Rev

293

185

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“…The IGF1R pathway is part of the insulin-related signaling network that plays a key role in development and metabolism (18). It is frequently activated in Ewing sarcoma and crucially implicated in disease progression (19)(20)(21).…”

Section: Introductionmentioning

confidence: 99%

Targeting the IGF1R/PI3K/AKT Pathway Sensitizes Ewing Sarcoma to BET Bromodomain Inhibitors

Loganathan

Tang

Holler

et al. 2019

Molecular Cancer Therapeutics

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Inhibitors of the bromodomain and extra-terminal domain (BET) family proteins modulate EWS-FLI1 activities in Ewing sarcoma. However, the efficacy of BET inhibitors as a monotherapy was moderate and transient in preclinical models. The objective of this study was to identify the mechanisms mediating intrinsic resistance to BET inhibitors and develop more effective combination treatments for Ewing sarcoma. Using a panel of Ewing sarcoma cell lines and patient-derived xenograft lines (PDX), we demonstrated that IGF1R inhibitors synergistically increased sensitivities to BET inhibitors and induced potent apoptosis when combined with BET inhibitors. Constitutively activated AKT significantly protected Ewing sarcoma cells against BET inhibitors, suggesting that IGF1R regulates responsiveness to BET inhibitors mainly through the PI3K/AKT pathway. Although two Ewing sarcoma cell lines were resistant to IGF1R inhibitors, they retained synergistic response to a combination of BET inhibitors and mTOR inhibitors, suggesting that BET proteins, when IGF1R is not functional, cross-talk with its downstream molecules. Furthermore, the combination of a BET inhibitor and an IGF1R inhibitor induced potent and durable response in xenograft tumors, whereas either agent alone was less effective. Taken together, our results suggest that IGF1R and the downstream PI3K/AKT/mTOR kinase cascade mediate intrinsic resistance to BET inhibitors in Ewing sarcoma. These results provide the proof-of-concept for combining BET inhibitors with agents targeting the IGF1R pathway for treating advanced Ewing sarcoma.

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“…Because most of these cell types are very rare (e.g. ~0.3% for MSCs, ≤0.05% for HSCs), we pooled the bone marrow from 5 mice per replicate, with 3-6 6 replicates per treatment group. We then assessed the transcriptome of each of these cell types via RNA-seq.…”

Section: Mesenchymal Stromal Cells Are the Primary Source Of Papp-a Imentioning

confidence: 99%

Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity

Mohrin

Liu

Zavala-Solorio

et al. 2020

Preprint

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Reducing insulin-like growth factor (IGF) signaling is one of the best conserved and characterized mechanisms to extend longevity. Pregnancy associated plasma protein A (PAPP-A) is a secreted metalloprotease that increases IGF availability by cleaving IGF binding proteins. PAPP-A inhibition reduces local IGF signaling, limits the progression of multiple age-related diseases, and extends lifespan, but the mechanisms behind these pleiotropic effects remains unknown. Here, we developed and utilized a PAPP-A neutralizing antibody to discover that adulthood inhibition of this protease reduced collagen and extracellular matrix (ECM) gene expression in multiple tissues in mice. Using bone marrow to explore this effect, we identified mesenchymal stromal cells (MSCs) as the source of PAPP-A and primary responders to PAPP-A inhibition. Short-term treatment with anti-PAPP-A reduced IGF signaling in MSCs, altered MSC expression of collagen/ECM, and decreased MSC number. This affected MSC-dependent functions, decreasing myelopoiesis and osteogenesis. Our data demonstrate that PAPP-A inhibition reduces the activity and number of IGF-dependent mesenchymal progenitor cells and their differentiated progeny, and that this reduction leads to functional changes at the tissue level. MSC-like cells are present in virtually all tissues, and aberrant collagen and ECM production from mesenchymal cells drives aspects of aging and age-related diseases, thus this may be a mechanism by which PAPP-A deficiency enhances lifespan and healthspan.SummaryInhibition of PAPP-A, a regulator of IGF signaling, decreases multi-tissue collagen and extracellular matrix gene expression and modulates mesenchymal stromal cell activity in murine bone marrow.

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Minireview: Were the IGF Signaling Inhibitors All Bad?

Cited by 80 publications

References 68 publications

The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer

The role of HER2, EGFR, and other receptor tyrosine kinases in breast cancer

Targeting the IGF1R/PI3K/AKT Pathway Sensitizes Ewing Sarcoma to BET Bromodomain Inhibitors

Pharmacological inhibition of longevity regulator PAPP-A restrains mesenchymal stromal cell activity

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