A surfaceome-based CRISPR-Cas9 screening reveals unexpected potent vulnerabilities for KRAS-addicted colorectal cancers
(2019) 62nd Annual Conference of the Canadian Society for Molecular Biosciences — Location: Montréal (Canada) (2.June.2019)
Files
No attached file found for this publication.
Details
- Authors
Aubert, Léo 
- Abstract
- Introduction: Despite significant progresses in cytotoxic chemo- and targeted therapies, metastatic colorectal cancer (CRC) remains incurable in most cases. The most promising therapeutic strategy for advanced CRC is the use of monoclonal antibodies that block activation of the epidermal growth factor receptor (EGFR). However, activating mutations in KRAS were shown to be common drivers of acquired resistance, and recent retrospective studies have shown that they negatively predict responsiveness to anti-EGFR therapy. Despite continuous efforts, oncogenic KRAS is still considered the “Higgs boson” of anticancer drugs targets, warranting the need for alternative therapeutic approaches. While the role of oncogenic KRAS on regulating intracellular signaling events is well described, much less is known about its potential impact on the cell surface proteome (surfaceome), which yet constitutes the predominant source of therapeutic targets for FDA-approved drugs. Methodology & Results: Herein, we have developed an unbiased target-discovery approach that relies on proteomic quantification of KRAS-dependent surfaceome changes and subsequent assessment of their functional relevance through both in vitro and in vivo CRISPR-Cas9 screenings. Interestingly, our proteomic data allowed the identification of over 350 cell surface proteins from which 35% and regulated in a KRAS-dependent manner, which partly rely on transcription. Further functional investigations of these candidates revealed new insights in the understanding of KRAS addiction towards nutrients macropinocytosis and collectively suggest alternative vulnerabilities for KRAS-mutated CRC cells. Conclusion: Thus, our study allows identification of new druggable targets in KRAS-addicted CRC and validates the surfaceome-based CRISPR-Cas9 approach as a potent strategy to determine oncogene-specific vulnerabilities.
- Affiliations
Citations
Aubert, L., Nandagopal, N., Nourreddine, S., Lavoie, G., Lévesque, K., Gaboury, L., Schramek, D., Meloche, S., Angers, S., & Roux, P. P. (2019). A surfaceome-based CRISPR-Cas9 screening reveals unexpected potent vulnerabilities for KRAS-addicted colorectal cancers. 62nd Annual Conference of the Canadian Society for Molecular Biosciences, Montréal (Canada). https://hdl.handle.net/2078.5/28766