Abstract
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide. The inability of chemotherapeutic drugs to selectively target HCC tumor cells because of their predominant resistant phenotype to most conventional anticancer agents bestows a major obstacle for the clinical management of HCC. In this report, we have examined and demonstrated the remarkable heterogeneity of expression of survivin and its phosphorylated active form (p-survivin) in HCC patients' tissues and cell lines. Furthermore, the expression of survivin and p-survivin in HCC cell lines was found to be associated with response to the small-molecule survivin suppressant YM155. Therefore, in the HCC cell lines that express elevated level of survivin and p-survivin, YM155 efficiently inhibited their proliferation, induced cell cycle arrest and apoptosis resulting in DNA damage through the dysregulation of cell-cycle checkpoint-related regulatory genes. Importantly, YM155 yielded significantly better therapeutic effect than sorafenib when tested in an orthotopic mouse model using patient-derived HCC xenografts with elevated survivin and p-survivin expression. Our results clearly demonstrated that the level of survivin and p-survivin expression could serve as molecular predictive biomarkers to select potential YM155-responsive patients, in a move towards delivering precision medicine for HCC patients.
Highlights
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide [1]
To evaluate the potential role of survivin as a therapeutic target for HCC, we systematically examined the expression of survivin in our dataset
The expression of survivin was found to be remarkably heterogeneous in HCC clinical samples, the detected signal intensity ranged from log22 to log29 (Fig. 1A)
Summary
Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related deaths worldwide [1]. Despite novel molecularly targeted therapies [4] and immunotherapy [5] are being developed, they are not very effective against advanced HCC. Sorafenib is the only FDAapproved molecular inhibitor for the systemic therapy of advanced HCC. Despite many ongoing efforts to explore non-surgical strategies to treat HCC, they have not been very successful and over 80% of the phase 3 molecularly-related targeted trials have failed [8]. The cause of genetic heterogeneity in cancer has not been well-established, there is the strategy approach to identify prognostic biomarkers and to decipher the associated molecular mechanisms to facilitate the selection of patients for molecularly-targeted therapies [11]
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