The role of Insulin Receptor in Cancer
The IGF-I receptor (IGF-IR) and its ligands (IGF-I and IGF-II) play a physiological role in growth and differentiation and are also involved in cancer growth and progression. The insulin receptor (IR), which shares high homology with the IGF-IR, has a predominant role in glucose metabolism. However, several studies have convincingly shown that the IR pathway is more intimately involved in cancer development and progression than previously thought. Recent evidences showing that insulin resistance and hyperinsulinemia are important risk factors for cancer have renewed the interest for these studies. One mechanism explaining the increased sensitivity of malignant cells to hyperinsulinemia is the frequent IR overexpression in cancer cells. Moreover, cancer cells commonly show an altered IR gene splicing, with predominant expression of IR-A, one of the two IR isoforms. IR-A binds not only insulin but also IGF-II and, therefore, it competes with IGF-IR for IGF-II binding. IGF-II, via IR-A, stimulates subtly different signaling than insulin. IR-A overexpression and high IGF-II autocrine production are important factors for both normal and cancer stem cells expansion and are often present in dedifferentiated malignancies. Finally, IR overexpression enhances cell responsiveness to IGF-I and IGF-II by participating to the formation of hybrid IR/IGF-IR receptors, which bind both IGFs.
Until very recently, only IGF-IR, but not IR, has been considered a target in cancer therapy. However, the results of the clinical first trials employing selective anti-IGF-IR drugs have been disappointing, with only a small subset of malignancies showing an objective response. Recent data have indicated that resistance to anti-IGF-IR drugs may include upregulation of IR isoform A and/or increased secretion of autocrine IGF-II. Therefore, cotargeting of IR and IGF-IR may prevent adaptative resistance to selective anti-IGF-IR drugs, especially in malignancies with high IR-A:IGF-IR ratio and autocrine IGF-II production.
Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.
Funding: This work was supported, however funding details unavailable.