Inhibition of JAK2 Signaling by TG101209 Enhances Radiotherapy in Lung Cancer Models

Abstract

Introduction Persistent STAT3 activation contributes to lung carcinogenesis. Survivin, one of STAT3-regulated genes, is antiapoptotic and confers cancer radioresistance. Methods We tested whether TG101209, a small-molecule inhibitor of JAK2 (a STAT3-activating tyrosine kinase), affected survivin expression and sensitized lung cancer to radiation. We investigated whether inhibition of JAK2 signaling with TG101209 can be used to reduce survivin expression and enhance radiosensitivity of lung cancer cells in vitro and tumor growth delay in vivo. JAK2 downstream signaling, including PI3-K/Akt and Ras/MAPK/ERK pathways, was also explored. Results TG101209 inhibited STAT3 activation and survivin expression, and sensitized HCC2429 (DER=1.34,p=0.002) and H460 (DER=1.09,p=0.006) cells to radiation in clonogenic assays. Radiation promoted phospho-Akt and phospho-ERK in H460 cells, while their levels were unchanged in HCC2429. After treatment with TG101209, phospho-ERK protein levels were reduced in both HCC2429 and H460 cells. HCC2429 cells transfected with K-Ras-12V mutant were more resistant to radiation- and TG101209-induced apoptosis than wild-type control cells. In vivo, addition of TG101209 to radiation in lung xenografts produced a significant tumor growth delay (>10 days) compared to radiation alone and was well tolerated. Immunohistochemistry staining of tumor sections showed that TG101209 increased apoptosis and decreased cell proliferation and vascular density, suggesting that TG101209 also has antiangiogenic effects. Conclusions TG101209 enhanced the effects of radiation in lung cancer in vitro and in vivo. This study suggests the potential utility of selecting lung cancer patients according to K-Ras mutation status for future clinical trials testing combination of TG101209 and radiotherapy.

PAK1 Tyrosine Phosphorylation Is Required to Induce Epithelial–Mesenchymal Transition and Radioresistance in Lung Cancer Cells

“…It has been demonstrated that the induction of c-jun expression in irradiated cells requires the activation of JAK3, but is impervious to the activation status of JAK1 and JAK2 (21). A recent study using TG101209, a small-molecule inhibitor of JAK2, found that JAK2 inhibition could be a promising strategy for lung cancer treatment (22). Therefore, it is important to define the role of the JAK2 pathway in irradiated solid tumors, because better therapies are desperately needed to treat these malignancies.…”

Biomarkers in Lung Cancer: Integration with Radiogenomics Data

“…The authors suggested that phosphorylation of ERK could contribute to the low levels of apoptosis induced by radiotherapy in mutated KRAS lung cancer cells. This work suggests that KRAS mutation status is one potential factor associated with increased resistance to radiation-induced apoptosis in lung cancer cells [70]. The same group has recently shown that the specific inhibition of JAK2 by the novel molecule TG101209, induces radiosensibility through inhibition of phosphorylation of STAT3 and reduced expression of survivin in HCC2429 lung cancer cells.…”

“…The same group has recently shown that the specific inhibition of JAK2 by the novel molecule TG101209, induces radiosensibility through inhibition of phosphorylation of STAT3 and reduced expression of survivin in HCC2429 lung cancer cells. Moreover, the inhibition of survivin by treatment with TG101209 in experiments in vivo, was related to increased apoptosis, reducing tumor proliferation and vascular density [70]. Lu et al demonstrated that overexpression of survivin leads to radioresistance in H460 lung cancer cells by inhibiting apoptosis and promoting cell survival, however, when survivin is inhibited by antisense oligonucleotides the cytotoxic effect of radiation is enhanced [71].…”

Immobilization of His-tagged kinase JAK2 onto the surface of a plasmon resonance gold disc modified with different copper (II) complexes

“…The most commonly used method to determine Janus kinase activity are radioisotope methods [4], phosphor specific antibodies [5], surface plasmon resonance [6] and fluorescence resonance energy transfer-based systems [7].…”