The use of IGF-IR inhibitors in cancer therapy : a potential approach for sensitizing tumor cells to ionizing radiation

This study focused on insulin-like growth factor I receptor (IGF-IR), considered as a promising therapeutic target for cancer treatment. We were in particular interested in the involvement of IGF-IR in tumor cells response to radiation and we tried to provide the rationale for a combined therapy of IFG4R inhibitors with radiation in order to improve the therapeutic outcome.

Lung cancer is the leading cause of cancer-related mortality for both men and women. Approximately 75% to 85% of all lung neoplasms are non-small cell lung cancers (NSCLC) and thoracic radiotherapy has been a common treatment for patients with locally advanced NSCLC. Malignant gliomas represent among the most treatment-refractory tumors encountered by clinicians. For several decades, the standard of care has represented maximal total resection, followed by radiation ± nitrosurea-based chemotherapy. Central nervous system and lung cancers constitute sites that are particularly difficult to irradiate due to a large number of conceptual difficulties, allowing them to be considered as 2 particularly interesting study models. For our in vitro studies we chose NSCLC and high grade glioma, (HGG) cell lines.

Our research demonstrated IGF-IR expression in a panel of cell lines that represented both tumor types. IGF-IR proved to be of importance in the survival of NSCLC cell lines and the receptor inhibition decreased cell proliferation by activating different apoptotic pathways. IGFIR inhibition combined with irradiation induced a higher degree of cell death, in association with an accumulation of cells in G2 phase and a concurrent reduction within the S phase, and thus indicated that IGF-IR was involved in the modulation of radiosensitivity in NSCLC cells. In contrast, in the HGG cell lines results showed the occurrence of a cross talk between IGF-IR and platelet-derived growth factor receptor (PDGFR). Dual targeting of IFG4R and PDGFR caused synergy in cell death and increased radiosensitivity.

In an attempt to elucidate the IGF-IR-mediated signal transduction pathways in response to radiation we observed a complex mechanism that was not only tumor type dependent but also cell type dependent. For the NSCLC cells we were able to demonstrate for the first time that ionizing radiation activated IFG4R IFG4R inhibition induced radiosensitivity via p38 kinase but not P13 kinase and this was a novel mechanism involving nuclear Ku86. In HGG cell lines radiosensitisation was found after dual inhibition of IFG4R and PDG17R and it was dependent on INK activation.

Our results suggest that IGF-IR targeting might be of importance when combined with radiation. In this context it is obvious that further characterization of the complex biological processes underlying radiation response is necessary in order to allow for biologically optimized and patient individualized radiation therapy.

List of scientific papers

I. Cosaceanu D, Carapancea M, Alexandru O, Budiu R, Martinsson HS, Starborg M, Vrabete M, Kanter L, Lewensohn R,Dricu A (2006). Comparison of three approaches for inhibiting insulin-like growth factor 1 receptor and their effects on NSCLC cell lines in vitro. Growth Factors. [Accepted]
https://doi.org/10.1080/08977190600702865

II. Cosaceanu D, Carapancea M, Castro J, Ekedahl J, Kanter L, Lewensohn R, Dricu A (2005). Modulation of response to radiation of human lung cancer cells following insulin-like growth factor 1 receptor inactivation. Cancer Lett. 222(2): 173-81.
https://doi.org/10.1016/j.canlet.2004.10.002

III. Cosaceanu D, Budiu R, Carapancea M, Castro J, Lewensohn R, Dricu A (2006). Ionizing radiation activates IGF-1R triggering a cytoprotective signaling by interfering with Ku-DNA binding and by modulating Ku86 expression via a p38 kinase dependent mechanism. Oncogene. [Accepted]
https://doi.org/10.1038/sj.onc.1210037

IV. Carapancea M, Cosaceanu D, Budiu R, Kwiecinska A, Tataranu L, Ciubotaru V, Alexandru O, Bäcklund M, Lewensohn L, Dricu A (2006). Dual targeting of IGF-1R and PDGFR inhibits proliferation in high grade gliomas cells and induces radiosensitivity in JNK-1 expressing cells. [Manuscript]