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 (dose enhancement ratio = 1.34, p = 0.002) and H460 (dose enhancement ratio = 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 KRAS-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 with 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 KRAS mutation status for future clinical trials testing combination of TG101209 and radiotherapy.

• Authors: Yunguang Sun, Luigi Moretti, Nicholas J Giacalone, Stephen Schleicher, Christina K Speirs, David P Carbone, Bo Lu
• Journal: Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer (J Thorac Oncol) Vol. 6 Issue 4 Pg. 699-706 (Apr 2011) ISSN: 1556-1380 [Electronic] United States
• PMID: 21325979 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• BIRC5 protein, human
• Cesium Radioisotopes
• Inhibitor of Apoptosis Proteins
• Pyrimidines
• Radiation-Sensitizing Agents
• STAT3 Transcription Factor
• STAT3 protein, human
• Sulfonamides
• Survivin
• TG101209
• JAK2 protein, human
• Janus Kinase 2
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Blotting, Western
• Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism, radiotherapy)
• Cell Proliferation (drug effects, radiation effects)
• Cesium Radioisotopes
• Female
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Janus Kinase 2 (antagonists & inhibitors, metabolism)
• Lung Neoplasms (drug therapy, metabolism, radiotherapy)
• Mice
• Mice, Nude
• Proto-Oncogene Proteins c-akt (metabolism)
• Pyrimidines (pharmacology)
• Radiation-Sensitizing Agents (pharmacology)
• STAT3 Transcription Factor (metabolism)
• Signal Transduction (drug effects)
• Sulfonamides (pharmacology)
• Survivin
• Tumor Cells, Cultured
• Tumor Stem Cell Assay
• X-Rays