Insulin-like growth factor (IGF) signaling in tumorigenesis and the development of cancer drug resistance

Abstract

One of the greatest obstacles to current cancer treatment efforts is the development of drug resistance by tumors. Despite recent advances in diagnostic practices and surgical interventions, many neoplasms demonstrate poor response to adjuvant or neoadjuvant radiation and chemotherapy. As a result, the prognosis for many patients afflicted with these aggressive cancers remains bleak. The insulin-like growth factor (IGF) signaling axis has been shown to play critical role in the development and progression of various tumors. Many basic science and translational studies have shown that IGF pathway modulators can have promising effects when used to treat various malignancies. There also exists a substantial body of recent evidence implicating IGF signaling dysregulation in the dwindling response of tumors to current standard-of-care therapy. By better understanding both the IGF-dependent and -independent mechanisms by which pathway members can influence drug sensitivity, we can eventually aim to use modulators of IGF signaling to augment the effects of current therapy. This review summarizes and synthesizes numerous recent investigations looking at the role of the IGF pathway in drug resistance. We offer a brief overview of IGF signaling and its general role in neoplasia, and then delve into detail about the many types of human cancer that have been shown to have IGF pathway involvement in resistance and/or sensitization to therapy. Ultimately, our hope is that such a compilation of evidence will compel investigators to carry out much needed studies looking at combination treatment with IGF signaling modulators to overcome current therapy resistance.

Augmentation of response to nab-paclitaxel by inhibition of insulin-like growth factor (IGF) signaling in preclinical pancreatic cancer models

“…Most of the tumorigenic effects of IGF signaling involves the binding of two ligands, IGF-1 and IGF-2, to IGF-1R, leading to the activation of several downstream signal transduction pathways including the phosphatidylinositol 3′-kinase (PI3K)/AKT and mitogen-activated protein kinase (MAPK) pathways [17]. Aberrant IGF signaling stimulates proliferation, differentiation, angiogenesis, metastasis, survival, and drug resistance in many cancers [18, 19], establishing this pathway as a generally promising therapeutic target. The IGF-1R pathway inhibition has been the subject of intensive anti-cancer drug discovery efforts and currently there are more than 30 active clinical trials evaluating anti-IGF-1R targeting agents, either alone or in various combinations (www.clinicaltrial.gov).…”

Inhibition of insulin‐like growth factor 1 receptor enhances the efficacy of sorafenib in inhibiting hepatocellular carcinoma cell growth and survival

“…It has been shown that IGF1R activation leads to both PI3/AKT and RAS/RAF/ERK activation 8. However, we found that knockdown of IGF1R or ceritinib inhibits only the activation of AKT but not ERK in HCC cells (Fig.…”

“…IGF1R is activated through ligand‐induced phosphorylation and subsequently phosphorylates and activates both the PI3K/AKT and Ras/mitogen‐activated protein kinase pathways 8. Activation of IGF1R is crucial for malignant transformation and the survival of malignant cells 8, 9, 10.…”

“…IGF1R is activated through ligand‐induced phosphorylation and subsequently phosphorylates and activates both the PI3K/AKT and Ras/mitogen‐activated protein kinase pathways 8. Activation of IGF1R is crucial for malignant transformation and the survival of malignant cells 8, 9, 10. For example, aberrant expression and activation of IGF1R contributes to increased survival of pancreatic cancer cells,11 and knockdown of IGF1R led to inhibition of proliferation, migration, and invasiveness of prostate cancer cells 12.…”

Growth factors and kinases in glioblastoma growth

“…Additionally, the IGF-IR pathway appears to be involved in glioma stem cells' ability to adapt to repeated radiation, leading to radio-resistant cells. However, radio-resistant tumors treated with IGF-IR inhibitors have resulted in a significant increase in radiosensitivity [83,84] . It has been reported that in an in vivo model, the invasion and proliferation of glioblastomas are significantly reduced by blocking IGF-IR, while showing an increase in apoptosis and a reduction in intratumoral vascularization at the same time [85,86] .…”