In vivo genome-wide CRISPR screen reveals breast cancer vulnerabilities and synergistic mTOR/Hippo targeted combination therapy

Meiou Dai, Gang Yan, Ni Wang, Girija Daliah, Ashlin M. Edick, Sophie Poulet, Julien Boudreault, Suhad Ali, Sergio A. Burgos and Jean-Jacques Lebrun ()
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Meiou Dai: McGill University Health Center, Cancer Research Program
Gang Yan: McGill University Health Center, Cancer Research Program
Ni Wang: McGill University Health Center, Cancer Research Program
Girija Daliah: McGill University Health Center, Cancer Research Program
Ashlin M. Edick: McGill University
Sophie Poulet: McGill University Health Center, Cancer Research Program
Julien Boudreault: McGill University Health Center, Cancer Research Program
Suhad Ali: McGill University Health Center, Cancer Research Program
Sergio A. Burgos: McGill University
Jean-Jacques Lebrun: McGill University Health Center, Cancer Research Program

Nature Communications, 2021, vol. 12, issue 1, 1-18

Abstract: Abstract Triple negative breast cancer (TNBC) patients exhibit poor survival outcomes and lack effective targeted therapies. Using unbiased in vivo genome-wide CRISPR screening, we interrogated cancer vulnerabilities in TNBC and identified an interplay between oncogenic and tumor suppressor pathways. This study reveals tumor regulatory functions for essential components of the mTOR and Hippo pathways in TNBC. Using in vitro drug matrix synergy models and in vivo patient-derived xenografts, we further establish the therapeutic relevance of our findings and show that pharmacological inhibition of mTORC1/2 and oncoprotein YAP efficiently reduces tumorigenesis in TNBC. At the molecular level, we find that while verteporfin-induced YAP inhibition leads to apoptosis, torin1-mediated mTORC1/2 inhibition promotes macropinocytosis. Torin1-induced macropinocytosis further facilitates verteporfin uptake, thereby greatly enhancing its pro-apoptotic effects in cancer cells. Overall, our study underscores the power and robustness of in vivo CRISPR genome-wide screens in identifying clinically relevant and innovative therapeutic modalities in cancer.

Date: 2021
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DOI: 10.1038/s41467-021-23316-4

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