RIP1 protects melanoma cells from apoptosis induced by BRAF/MEK inhibitors

Fu Xi Lei,Xiao Ying Liu,Lei Jin,Margaret Farrelly,Su Tang Guo,Xin Han Zhao,Fritz Lai,Xu Dong Zhang,Xu Guang Yan

doi:10.1038/s41419-018-0714-7

Abstract

Many recent studies have uncovered the necessary role for the receptor-interacting protein kinase 1 (RIP1) in regulating apoptosis and necrosis that cells undergo in response to various cellular stresses. However, the functional significance of RIP1 in promoting cancer cell survival remains poorly understood. Here, we report that RIP1 was upregulated and contributed to both intrinsic and acquired resistance of melanoma cells to BRAF/MEK inhibitors through activation of NF-κB. Strikingly, Snail1-mediated suppression of CYLD played a crucial role in promoting RIP1 expression upon ERK activation, particularly, in melanoma cells with acquired resistance to BRAF inhibitors. In addition, RIP1 kinase activity was not required for melanoma cells to survive BRAF/MEK inhibition as RIP1 mediated NF-κB activation through its intermediate domain. Collectively, our findings reveal that targeting RIP1 in combination with BRAF/MEK inhibitors is a potential approach in the treatment of the disease.

Highlights

Introduction TargetingBRAF, MEK, and co-targeting BRAF and MEK using specific inhibitors have become the standard of care for patients with late-stage mutant BRAF melanomas[1]
We show that receptor-interacting protein kinase 1 (RIP1) protects human melanoma cells from apoptosis induced by BRAF/MEK inhibitors, and that this is mediated by activation of NF-κB
Treatment with the general caspase inhibitor z-VAD-fmk abolished reduction in cell viability (Fig. 1c). These results indicate that RIP1 plays a role in intrinsic resistance of melanoma cells to apoptosis induced by BRAF/MEK inhibitors

Summary

Introduction

Introduction TargetingBRAF, MEK, and co-targeting BRAF and MEK using specific inhibitors have become the standard of care for patients with late-stage mutant BRAF melanomas[1]. Regression of metastatic BRAF melanomas is a common response to administration of BRAF/MEK inhibitors in patients[9], suggesting that apoptosis induction may be a major biological consequence of inhibition of the pathway that causes remission of melanomas[10]. In support of this notion, we have previously shown that induction of apoptosis is a major determinant of long-term responses of BRAFV600E melanoma cells to mutant BRAF inhibitors[9]. Molecular mechanisms responsible for resistance of melanoma cells to apoptosis induced by inhibition of the pathway remain to be fully understood

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Conclusion