Somatic Hypermutation of the YAP Oncogene in a Human Cutaneous Melanoma.

Xiaomeng Zhang,Lie Yang,Anthony T Papenfuss,Pacman Szeto,Jian Zhong Tang,Christopher Mintoff,Georgina V Long,Grant A Mcarthur,Evangeline Shaw,Mark Shackleton,Ismael A Vergara,Helen Rizos,Kieran F Harvey,Lachlan Mcintosh,Katrina A Mitchell,Youfang Zhang,Andrew Colebatch,Nicholas Hayward

doi:10.1158/1541-7786.mcr-18-0407

Abstract

Melanoma is usually driven by mutations in BRAF or NRAS, which trigger hyperactivation of MAPK signaling. However, MAPK-targeted therapies are not sustainably effective in most patients. Accordingly, characterizing mechanisms that co-operatively drive melanoma progression is key to improving patient outcomes. One possible mechanism is the Hippo signaling pathway, which regulates cancer progression via its central oncoproteins YAP and TAZ, although is thought to be only rarely affected by direct mutation. As YAP hyperactivation occurs in uveal melanoma, we investigated this oncogene in cutaneous melanoma. YAP protein expression was elevated in most benign nevi and primary cutaneous melanomas but present at only very low levels in normal melanocytes. In patient-derived xenografts and melanoma cell lines, we observed variable reliance of cell viability on Hippo pathway signaling that was independent of TAZ activity and also of classical melanoma driver mutations such as BRAF and NRAS. Finally, in genotyping studies of melanoma, we observed the first ever hyperactivating YAP mutations in a human cancer, manifest as seven distinct missense point mutations that caused serine to alanine transpositions. Strikingly, these mutate four serine residues known to be targeted by the Hippo pathway and we show that they lead to hyperactivation of YAP. IMPLICATIONS: Our studies highlight the YAP oncoprotein as a potential therapeutic target in select subgroups of melanoma patients, although successful treatment with anti-YAP therapies will depend on identification of biomarkers additional to YAP protein expression.

Highlights

Recent spectacular advances in treatment of melanoma, a common and deadly form of skin cancer, have leveragedNote: Supplementary data for this article are available at Molecular Cancer Research Online.X
In patient-derived xenografts (PDX) and cell lines, we found that melanoma cells rely on YAP for survival only variably, that this is independent of mutations in BRAF and NRAS, and that TAZ does not consistently compensate for YAP depletion in maintaining melanoma cell viability
In parallel studies (Supplementary Fig. S1) of melanoma cell lines representing mutant BRAF, mutant NRAS and BRAF/NRAS double-wild-type genotypes, immunoblotting of YAP and TAZ showed ubiquitous expression of YAP, with phospho-S127-YAP levels proportional to total YAP

Summary

Introduction

Recent spectacular advances in treatment of melanoma, a common and deadly form of skin cancer, have leveraged. Whereas YAP and TAZ inhibited invasion in 1205Lu and SKMEL28 cells [24], heterogeneity in clonogenic growth amongst lines was noted upon TAZ knockdown This raises the possibility that these oncoproteins might regulate malignant behaviors in only some cancers. It is unknown whether YAP and TAZ, which are paralogous proteins, can compensate for each other's inhibition. Both these possibilities have implications for development of inhibitors of YAP- or TAZ-mediated transcription To address these issues, we used melanoma patient samples, patient-derived xenografts (PDX), and cell lines to investigate systematically the Hippo pathway in melanoma. We report the first obvious gain-of-function missense mutations in the YAP oncogene in human cancer and implicate the Hippo pathway as a potential therapeutic target in a subset of melanomas

Materials and Methods

Results

Discussion

Disclosure of Potential Conflicts of Interest