Daehyeon Seong^a,1, Manhyung Jeong^a,1, Jinho Seo^a,b, Ji-Yoon Lee^c, Chi Hyun Hwang^a, Ho-Chul Shin^d, Jeong Yoon Shin^a, Young Woo Nam^a, Jeong Yeon Jo^e, Haeseung Lee^f, Hye-Jung Kim^g, Hwa-Ryeon Kim^a, Ji Hoon Oh^a, Sang-Jun Ha^a, Seung Jun Kim^d, Jae-Seok Roe^a, Wankyu Kim^f, June-Won Cheong^h, Kwang-Hee Bae^c, Sang Chul Lee^c, Andrew Oberstⁱ, Peter Vandenabeele^j,k, Dong Hoon Shin^e, Eun-Woo Lee^c,2, and Jaewhan Song^a,2

^aDepartment of Biochemistry, College of Life Science and Biotechnology, Yonsei University, 120-749 Seoul, Republic of Korea; ^bEnvironmental Diseases Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea; ^cMetabolic Regulation Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea; ^dDisease Target Structure Research Center, Korea Research Institute of Bioscience and Biotechnology, 34141 Daejeon, Republic of Korea; ^eResearch Institute, Department of Cancer Biomedical Science, Graduate School of Cancer Science and Policy, National Cancer Center, 10408 Goyang, Republic of Korea; ^fDepartment of Life Sciences, Ewha Research Center for Systems Biology, Ewha Womans University, 03760 Seoul, Republic of Korea; ^gNew Drug Development Center, Korea Biotechnology Industry Organization Osong Medical Innovation Foundation, 28160 Cheongju-si, Republic of Korea; ^hDivision of Hematology, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 03722 Seoul, Republic of Korea; ⁱDepartment of Immunology, University of Washington, Seattle, WA 98109; ^jVlaams Instituut voor Biotechnologie-University of Ghent Center for Inflammation Research, Vlaams Instituut voor Biotechnolgie, 9052 Ghent, Belgium; and ^kDepartment of Biomedical Molecular Biology, Ghent University, 9000 Ghent, Belgium

¹D.S. and M.J. contributed equally to this work.
²To whom correspondence may be addressed.

The underlying mechanism of necroptosis in relation to cancer is still unclear. Here, MYC, a potent oncogene, is an antinecroptotic factor that directly suppresses the formation of the RIPK1–RIPK3 complex. Gene set enrichment analyses reveal that the MYC pathway is the most prominently down-regulated signaling pathway during necroptosis. Depletion or deletion of MYC promotes the RIPK1–RIPK3 interaction, thereby stabilizing the RIPK1 and RIPK3 proteins and facilitating necroptosis. Interestingly, MYC binds to RIPK3 in the cytoplasm and inhibits the interaction between RIPK1 and RIPK3 in vitro. Furthermore, MYC-nick, a truncated form that is mainly localized in the cytoplasm, prevented TNF-induced necroptosis. Finally, down-regulation of MYC enhances necroptosis in leukemia cells and suppresses tumor growth in a xenograft model upon treatment with birinapant and emricasan. MYC-mediated suppression of necroptosis is a mechanism of necroptosis resistance in cancer, and approaches targeting MYC to induce necroptosis represent an attractive therapeutic strategy for cancer.

MYC, RIPK3, TNF-α, necroptosis