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

• Published in: Nature communications Vol. 12; no. 1; p. 3055
• Main Authors: Dai, Meiou, Yan, Gang, Wang, Ni, Daliah, Girija, Edick, Ashlin M., Poulet, Sophie, Boudreault, Julien, Ali, Suhad, Burgos, Sergio A., Lebrun, Jean-Jacques
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 24.05.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 13/109; 13/2; 13/31; 13/51; 13/95; 14/63; 38/43; 42/47; 45/23; 45/41; 631/67/1347; 64/60; 692/4028/67/69; 96/1; 96/106; 96/2; Apoptosis; Breast cancer; Combination therapy; CRISPR; Genomes; Humanities and Social Sciences; In vivo methods and tests; Medical innovations; multidisciplinary; Pharmacology; Science; Science (multidisciplinary); TOR protein; Tumor suppressor genes; Tumorigenesis; Tumors; Xenografts; Xenotransplantation; Yes-associated protein
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-021-23316-4

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. Triple negative breast cancer (TNBC) lack effective therapies. Here, through an in vivo genome-wide CRISPR screen in TNBCs, the authors identify tumorigenic functions for components of the mTORC1/2 complex and of the YAP/Hippo pathway, and demonstrate that pharmacological inhibition of mTOR and YAP reduces tumour growth in vivo.