Blockade of TGF-β Signaling by the TGFβR-I Kinase Inhibitor LY2109761 Enhances Radiation Response and Prolongs Survival in Glioblastoma

Abstract

Glioblastoma multiforme (GBM) is a highly aggressive primary brain tumor that tends to be resistant to the ionizing radiotherapy used to treat it. Because TGF-b is a modifier of radiation responses, we conducted a preclinical study of the antitumor effects of the TGF-b receptor (TGFbR) I kinase inhibitor LY2109761 in combination with radiotherapy. LY2109761 reduced clonogenicity and increased radiosensitivity in GBM cell lines and cancer stem-like cells, augmenting the tumor growth delay produced by fractionated radiotherapy in a supra-additive manner in vivo. In an orthotopic intracranial model, LY2109761 significantly reduced tumor growth, prolonged survival, and extended the prolongation of survival induced by radiation treatment. Histologic analyses showed that LY2109761 inhibited tumor invasion promoted by radiation, reduced tumor microvessel density, and attenuated mesenchymal transition. Microarray-based gene expression analysis revealed signaling effects of the combinatorial treatments that supported an interpretation of their basis. Together, these results show that a selective inhibitor of the TGFbR-I kinase can potentiate radiation responses in glioblastoma by coordinately increasing apoptosis and cancer stem-like cells targeting while blocking DNA damage repair, invasion, mesenchymal transition, and angiogenesis. Our findings offer a sound rationale for positioning TGFbR kinase inhibitors as radiosensitizers to improve the treatment of glioblastoma. Cancer Res; 71(23); 7155-67. Ó2011 AACR.

Signaling Receptors for TGF-β Family Members

“…These compounds often compete with binding of ATP to the ATP-binding site of the kinase, and several of them inhibit the TbRI kinase selectively, but often also inhibit the activin type I receptor ALK-4 and the nodal type I receptor ALK-7 (Yingling et al 2004). TbRI kinase inhibitors have been shown, in animal models, to inhibit invasion and metastasis of, for example, breast cancer cells (Bandyopadhyay et al 2006;Ge et al 2006;Ehata et al 2007;Liu et al 2012), melanoma cells (Mohammad et al 2011), glioma cells (Uhl et al 2004;Zhang et al 2011), and mesothelioma cells (Suzuki et al 2007). The effect of the inhibitors include inhibition of mesenchymal transition of the tumor cells, activation of the immune system, inhibition of angiogenesis, inhibition of osteolysis preventing bone metastasis, and normalization of tumor stroma.…”

Targeting TGF-β Signaling for Therapeutic Gain

“…There has been considerable interest in combining TGF-b pathway inhibition and radiotherapy (Anscher et al 2008;Bouquet et al 2011;Zhang et al 2011). Radiation physically activates the latent TGF-b complex in cell culture and in vivo (Barcellos-Hoff 1993;BarcellosHoff et al 1994).…”

TGFβ1 Protects Cells from γ-IR by Enhancing the Activity of the NHEJ Repair Pathway

“…Others have also reported similar results. TGFb1 inhibition before g-irradiation attenuated the DNA damage response, increased cell death and delayed tumor growth (4,5), and TGFb1 pretreatment protected Mv1Lu epithelial cells from g-irradiation, an effect that was dependent on de novo protein synthesis (19). Moreover, high levels of TGFb production in gliomainitiating cells in oncosphere culture provide a clonogenic benefit to this population following radiation exposure (20).…”

“…A number of researchers have described a protective role of TGFb against ionizing radiation (IR), reporting that inhibition of TbRI increases radiosensitivity (4,5) and attenuates g-irradiationinduced ATM kinase activity (6). ATM is activated in response to DNA double-strand breaks (DSB) caused by IR and, in turn, phosphorylates numerous substrates, which activate a complex program that controls cell-cycle checkpoints, apoptosis, and genomic integrity.…”