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Published on: May 1, 2019
Inhibiting casein kinase 2 overcomes paclitaxel resistance in gastric cancer
Minkyu Jung1,2, Kyu Hyun Park2, Hyun Myong Kim2
1Division of Medical Oncology, Department of Internal Medicine, Yonsei Cancer Center, Yonsei University College of Medicine, 51 Yonsei-Ro, Seodaemun-gu, Seoul, 120-752, Korea.
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.
Insights
Casein kinase 2 (CK2) activation correlates with paclitaxel resistance in gastric cancer. Combining a CK2 inhibitor (CX-4945) with paclitaxel shows promise for overcoming this resistance.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Casein kinase 2 (CK2) activation is linked to tumor proliferation and chemotherapy resistance.
- Understanding the role of CK2 in gastric cancer (GC) paclitaxel resistance is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the mechanistic basis of CK2 activation in paclitaxel resistance in gastric cancer.
- To evaluate the therapeutic potential of a CK2 inhibitor, CX-4945, in combination with paclitaxel for gastric cancer.
Main Methods:
- CK2 expression was assessed in 59 advanced GC patients treated with paclitaxel.
- The efficacy of CX-4945 and paclitaxel was evaluated in GC cell lines and a xenograft model.
- Phosphatidylinositol 3-kinase/AKT signaling was analyzed in response to combination therapy.
Main Results:
- High CK2 expression in patients correlated with lower disease control rates and shorter progression-free survival.
- CK2 protein expression was associated with paclitaxel sensitivity in GC cell lines.
- Combination therapy with CX-4945 and paclitaxel demonstrated synergistic antiproliferative effects and suppressed tumor growth in vivo.
Conclusions:
- CK2 activation is associated with paclitaxel resistance in gastric cancer.
- CX-4945 combined with paclitaxel represents a potential therapeutic strategy for overcoming paclitaxel resistance in GC.
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