Theranostics 2018; 8(14):3737-3750. doi:10.7150/thno.25487

Research Paper

Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma

Chuan Xing Wu1✉, Xiao Qi Wang1,2✉, Siu Ho Chok1, Kwan Man1, Simon Hing Yin Tsang1, Albert Chi Yan Chan1, Ka Wing Ma1, Wei Xia1, Tan To Cheung1

1. Department of Surgery, The University of Hong Kong, Hong Kong.
2. Department of Medicine, The University of Hong Kong, Hong Kong.

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Citation:
Wu CX, Wang XQ, Chok SH, Man K, Tsang SHY, Chan ACY, Ma KW, Xia W, Cheung TT. Blocking CDK1/PDK1/β-Catenin signaling by CDK1 inhibitor RO3306 increased the efficacy of sorafenib treatment by targeting cancer stem cells in a preclinical model of hepatocellular carcinoma. Theranostics 2018; 8(14):3737-3750. doi:10.7150/thno.25487. Available from http://www.thno.org/v08p3737.htm

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Abstract

Rationale: Hepatocellular carcinoma (HCC) is an aggressive malignant solid tumor wherein CDK1/PDK1/β-Catenin is activated, suggesting that inhibition of this pathway may have therapeutic potential.

Methods: CDK1 overexpression and clinicopathological parameters were analyzed. HCC patient-derived xenograft (PDX) tumor models were treated with RO3306 (4 mg/kg) or sorafenib (30 mg/kg), alone or in combination. The relevant signaling of CDK1/PDK1/β-Catenin was measured by western blot. Silencing of CDK1 with shRNA and corresponding inhibitors was performed for mechanism and functional studies.

Results: We found that CDK1 was frequently augmented in up to 46% (18/39) of HCC tissues, which was significantly associated with poor overall survival (p=0.008). CDK1 inhibitor RO3306 in combination with sorafenib treatment significantly decreased tumor growth in PDX tumor models. Furthermore, the combinatorial treatment could overcome sorafenib resistance in the HCC case #10 PDX model. Western blot results demonstrated the combined administration resulted in synergistic down-regulation of CDK1, PDK1 and β-Catenin as well as concurrent decreases of pluripotency proteins Oct4, Sox2 and Nanog. Decreased CDK1/PDK1/β-Catenin was associated with suppression of epithelial mesenchymal transition (EMT). In addition, a low dose of RO3306 and sorafenib combination could inhibit 97H CSC growth via decreasing the S phase and promoting cells to enter into a Sub-G1 phase. Mechanistic and functional studies silencing CDK1 with shRNA and RO3306 combined with sorafenib abolished oncogenic function via downregulating CDK1, with downstream PDK1 and β-Catenin inactivation.

Conclusion: Anti-CDK1 treatment can boost sorafenib antitumor responses in PDX tumor models, providing a rational combined treatment to increase sorafenib efficacy in the clinic.

Keywords: cancer stem cells, hepatocellular carcinoma, PDX models, CDK1 inhibitor, RO3306, sorafenib