Danielle Braggio1,2, David Koller1,2, Feng Jin3, Nanda Siva4, Abeba Zewdu1,2, Gonzalo Lopez1,2, Kara Batte1,2, Lucia Casadei1,2, Meng Welliver3, Anne M Strohecker2,5,6, Dina Lev7,8, Raphael E Pollock1,2. 1. Program in Translational Therapeutics, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. 2. Department of Surgery, The Ohio State University, Columbus, Ohio. 3. Department of Radiation Oncology, The Ohio State University, Columbus, Ohio. 4. Department of Chemical and Biomedical Engineering, West Virginia University Statler College of Engineering and Mineral Resources, Morgantown, West Virginia. 5. Program in Molecular Biology and Cancer Genetics, The James Comprehensive Cancer Center, The Ohio State University, Columbus, Ohio. 6. Department of Cancer Biology and Genetics, College of Medicine, The Ohio State University, Columbus, Ohio. 7. Department of General Surgery B, Sheba Medical Center, Tel Aviv, Israel. 8. Tel Aviv University, Tel Aviv, Israel.
Abstract
BACKGROUND: Desmoid tumors (DTs) are rare and understudied fibroblastic lesions that are frequently recurrent and locally invasive. DT patients often experience chronic pain, organ dysfunction, decrease in quality of life, and even death. METHODS: Sorafenib has emerged as a promising therapeutic strategy, which has led to the first randomized phase 3 clinical trial devoted to DTs. Concurrently, we conducted a comprehensive analysis of sorafenib efficacy in a large panel of desmoid cell strains to probe for response mechanism. RESULTS: We found distinctive groups of higher- and lower-responder cells. Clustering the lower-responder group, we observed that CTNNB1 mutation was determinant of outcome. Our results revealed that a lower dose of sorafenib was able to inhibit cell viability, migration, and invasion of wild-type and T41A-mutated DTs. Apoptosis induction was observed in those cells after treatment with sorafenib. On the other hand, the lower dose of sorafenib was not able to inhibit cell viability, migration, or invasion or to induce apoptosis in the S45F-mutated DTs. The investigation of autophagy showed the dependency of S45F-mutated DTs on this pathway as a part of cell survival mechanism. Significantly, when autophagy was inhibited genetically or pharmacologically in the S45F mutant cell strains, sensitivity to sorafenib was restored. CONCLUSIONS: Our findings suggest that the response to sorafenib differs when comparing S45F-mutated DTs and T41A-mutated or wild-type DTs. Furthermore, the combination of hydroxychloroquine and sorafenib enhances the antiproliferative and proapoptotic effects in S45F-mutated DT cells, suggesting that profiling β-catenin status could guide clinical management of desmoid patients who are considering sorafenib treatment.
BACKGROUND:Desmoid tumors (DTs) are rare and understudied fibroblastic lesions that are frequently recurrent and locally invasive. DT patients often experience chronic pain, organ dysfunction, decrease in quality of life, and even death. METHODS:Sorafenib has emerged as a promising therapeutic strategy, which has led to the first randomized phase 3 clinical trial devoted to DTs. Concurrently, we conducted a comprehensive analysis of sorafenib efficacy in a large panel of desmoid cell strains to probe for response mechanism. RESULTS: We found distinctive groups of higher- and lower-responder cells. Clustering the lower-responder group, we observed that CTNNB1 mutation was determinant of outcome. Our results revealed that a lower dose of sorafenib was able to inhibit cell viability, migration, and invasion of wild-type and T41A-mutated DTs. Apoptosis induction was observed in those cells after treatment with sorafenib. On the other hand, the lower dose of sorafenib was not able to inhibit cell viability, migration, or invasion or to induce apoptosis in the S45F-mutated DTs. The investigation of autophagy showed the dependency of S45F-mutated DTs on this pathway as a part of cell survival mechanism. Significantly, when autophagy was inhibited genetically or pharmacologically in the S45F mutant cell strains, sensitivity to sorafenib was restored. CONCLUSIONS: Our findings suggest that the response to sorafenib differs when comparing S45F-mutated DTs and T41A-mutated or wild-type DTs. Furthermore, the combination of hydroxychloroquine and sorafenib enhances the antiproliferative and proapoptotic effects in S45F-mutated DT cells, suggesting that profiling β-catenin status could guide clinical management of desmoidpatients who are considering sorafenib treatment.
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