Journal article
Identification of resistance mechanisms to small-molecule inhibition of TEAD-regulated transcription
A Kulkarni, V Mohan, TT Tang, L Post, YC Chan, M Manning, N Thio, BL Parker, MA Dawson, J Rosenbluh, JHA Vissers, KF Harvey
EMBO Reports | SPRINGERNATURE | Published : 2024
Abstract
The Hippo tumor suppressor pathway controls transcription by regulating nuclear abundance of YAP and TAZ, which activate transcription with the TEAD1-TEAD4 DNA-binding proteins. Recently, several small-molecule inhibitors of YAP and TEADs have been reported, with some entering clinical trials for different cancers with Hippo pathway deregulation, most notably, mesothelioma. Using genome-wide CRISPR/Cas9 screens we reveal that mutations in genes from the Hippo, MAPK, and JAK-STAT signaling pathways all modulate the response of mesothelioma cell lines to TEAD palmitoylation inhibitors. By exploring gene expression programs of mutant cells, we find that MAPK pathway hyperactivation confers resi..
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Awarded by Australian Cancer Research Foundation
Funding Acknowledgements
We thank Avni Anand, Luis Malaver-Ortega, Henry Beetham, and members of the Harvey lab for discussions and comments on the manuscript, and A. Chand, T. John, and M. Shackleton for reagents. KFH was supported by a Senior Research Fellowship (APP1078220) and Investigator grant (APP1194467) from the National Health and Medical Research Council of Australia (NHMRC). AK was partly supported by an Australian Government Research Training Program Scholarship and Rosie Lew Peter MacCallum Cancer Foundation Postgraduate Award. This research was supported by a Lyall Watts Mesothelioma Research Grant from the Cancer Council Victoria (APP1157737) and the Peter MacCallum Cancer Foundation. We acknowledge the Monash Functional Genomics Platform and the following Peter MacCallum Cancer Centre core facilities: Flow Cytometry, Victorian Centre for Functional Genomics, Bioinformatics, Research Laboratory Support Services, and Centre for Advanced Histology and Microscopy, and support to them from the Peter MacCallum Cancer Foundation and the Australian Cancer Research Foundation.