Presentation description

Hepatocellular carcinoma (HCC) is the most common form of primary liver cancer and is the third-most deadly cancer in the U.S. with a dismal five-year survival rate of only 18%. HCC is typically diagnosed at intermediate to late stages, precluding curative treatment. Intermediate-stage HCC is often treated with doxorubicin-based trans-arterial chemoembolization (TACE). However, due to extreme chemoresistance, HCC relapse following TACE is common. To become resistant, HCC cells can undergo epithelial-mesenchymal transition (EMT), a conserved developmental program that promotes survival, cell motility, and invasiveness. Thus, EMT has emerged as an attractive target to overcome resistance and prevent metastasis. The 518 human protein kinases, i.e., the kinome, are critical for cell signaling including the cancer cell EMT. Kinases are also highly druggable and may, therefore, serve as viable drug targets to reverse EMT and prevent chemoresistance. We hypothesize that mesenchymal HCC cells rewire their kinome to adapt to chemotherapy, and that inhibiting adaptive kinases reduces resistance.
In this study, we used our in-house developed, mass spectrometry (MS)-based kinomics platform to assess kinome rewiring in the mesenchymal HCC cells treated with sub-lethal doxorubicin. We found that the mesenchymal HCC cell line SNU387 systematically activated a network of kinases involved in cell survival (MERTK, HCK) and the DNA damage response (CHEK1, NEK2, AURKB). Gene set enrichment analysis (GSEA) confirmed that cell proliferation, survival, and DNA damage response pathways were upregulated. This suggested that mesenchymal HCC cells adapt to doxorubicin treatment by simultaneously inhibiting apoptosis and enhancing their DNA damage repair. Thus, combining doxorubicin with inhibitors of tyrosine kinases that promote survival, and DNA damage checkpoint kinase inhibitors may prevent HCC adaption to doxorubicin/TACE treatment.