Exploring novel SRC-regulated pathways in IDH mutant intrahepatic cholangiocarcinoma

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PROJECT SUMMARY/ABSTRACT Intrahepatic cholangiocarcinoma (ICC) is a highly lethal form of liver cancer which has been rising in incidence worldwide and carries a prognosis of under one year. The current standard of care for the majority of patients who present with advanced stage disease remains toxic combination chemotherapy. However, recent genetic studies have determined that many ICC tumors harbor mutations which can be treated with ‘targeted therapies.’ Such targeted therapies may often be given as a pill form and generally have fewer side effects than chemotherapy. As a result, there is now hope for a shift in the therapeutic paradigm for ICC, from the current standard of combination chemotherapy for all patients to targeted therapies for ICC patients who have ‘targetable’ mutations. The most common of these mutations in ICC fall within a gene called isocitrate dehydrogenase (IDH). Although clinical trials are currently underway to evaluate the efficacy of targeted therapy in IDH mutant ICC, early trial results suggest that sequential or combinatorial strategies will be needed to induce durable remissions in this disease. In our previous work, we used laboratory models of IDH mutant ICC such as human cancer cell lines and patient-derived xenografts (PDXs) to show that IDH mutant ICC cells are extremely sensitive to a targeted therapy called dasatinib. Dasatinib acts to kill IDH mutant ICC cells by inhibiting the activity of a protein called SRC. Interestingly, this dependence on SRC activity appears to be highly specific to IDH mutant ICC cells when compared to cells from ICC tumors that do not have IDH mutations or tumor cells from any other cancer tested. This proposal aims to couple traditional molecular biology and biochemical approaches with advanced technologies such as phosphoproteomics, CRISPR/Cas9-mediated genome editing, and polyribosome profiling to uncover the unique functional role that SRC plays in IDH mutant ICC and to elucidate why this specific genetic subset of ICC is so dependent on SRC activity. This work will be benefited by our unique reagents, consisting of a large panel of ICC model systems, including human cell lines and PDXs as well as the rich and highly collaborative scientific environment at the Fred Hutchinson Cancer Research Institute. Ultimately, the long-term goal of our work is to improve our understanding of the distinct biology underlying these tumors in hopes of developing more effective, and less toxic, therapeutic options for ICC patients.