Minkyu Jung1,2, Kyu Hyun Park2, Hyun Myong Kim2, Tae Soo Kim2, Xianglan Zhang3,4, Sun-Mi Park5, Seung-Hoon Beom1, Hyo Song Kim1, Jae-Ho Cheong6, Hyun Cheol Chung1,2, John Soong7, Shu-Chuan Lin8, Sun Young Rha9,10. 1. Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 51 Yonsei-Ro, Seodaemun-gu, Seoul, 120-752, Korea. 2. Song-Dang Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea. 3. Oral Cancer Research Institute, Yonsei University College of Dentistry, Seoul, Korea. 4. Department of Pathology, Yanbian University Hospital, Yanji, China. 5. Molecular Pharmacology Program and Center for Cell Engineering, Memorial Sloan Kettering Cancer Center, New York, USA. 6. Department of Surgery, Yonsei University College of Medicine, Seoul, Korea. 7. Senhwa Biosciences Corporation, San Diego, CA, USA. 8. Senhwa Biosciences, Inc., New Taipei City, Taiwan, ROC. 9. Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 51 Yonsei-Ro, Seodaemun-gu, Seoul, 120-752, Korea. rha7655@yuhs.ac. 10. Song-Dang Institute for Cancer Research, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea. rha7655@yuhs.ac.
Abstract
PURPOSE: Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association between CK2 activation and paclitaxel resistance in a gastric cancer (GC). EXPERIMENTAL DESIGN: CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model. RESULTS: Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%, p = 0.017) and shorter progression-free survival (2.8 vs. 4.8 months, p = 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities. CONCLUSIONS: These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.
PURPOSE:Casein kinase (CK) 2 activation has been implicated in the proliferation of various tumor types and resistance to chemotherapy. We investigated the mechanistic basis for the association between CK2 activation and paclitaxel resistance in a gastric cancer (GC). EXPERIMENTAL DESIGN: CK2 expression was evaluated in 59 advanced GC patients treated with paclitaxel as the second-line therapy. The efficacy of a CK2 inhibitor, CX-4945, and paclitaxel was evaluated in GC cell lines and a xenograft model. RESULTS:Patients with high CK2 expression (29/59, 39%) showed lower disease control rates (47.7% vs. 72.3%, p = 0.017) and shorter progression-free survival (2.8 vs. 4.8 months, p = 0.009) than patients with low CK2 expression. CK2 protein expression was associated with sensitivity to paclitaxel in 49 GC cell lines. Combination therapy with CX-4945 and paclitaxel exerted synergistic antiproliferative effects and inhibited the downregulation of phosphatidylinositol 3-kinase/AKT signaling in SNU-1 cells. In the SNU-1 xenograft model, the combination treatment was significantly superior to either single agent, suppressing tumor growth without notable toxicities. CONCLUSIONS: These results demonstrated that CK2 activation was related to paclitaxel resistance and that CX-4945 in combination with paclitaxel could be used as a potential treatment for paclitaxel resistance in GC.
Entities:
Keywords:
Casein kinase 2; Drug resistance; Gastric cancer; Paclitaxel
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