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Publication

CRISPR-induced RASGAP deficiencies in colorectal cancer organoids reveal that only loss of NF1 promotes resistance to EGFR inhibition.

Oncotarget | 2019

Anti-EGFR therapy is used to treat metastatic colorectal cancer (CRC) patients, for which initial response rates of 10-20% have been achieved. Although the presence of HER2 amplifications and oncogenic mutations in KRAS, NRAS, and BRAF are associated with EGFR-targeted therapy resistance, for a large population of CRC patients the underlying mechanism of RAS-MEK-ERK hyperactivation is not clear. Loss-of-function mutations in RASGAPs are often speculated in literature to promote CRC growth as being negative regulators of RAS, but direct experimental evidence is lacking. We generated a CRISPR-mediated knock out panel of all RASGAPs in patient-derived CRC organoids and found that only loss of NF1, but no other RASGAPs e.g. RASA1, results in enhanced RAS-ERK signal amplification and improved tolerance towards limited EGF stimulation. Our data suggests that NF1-deficient CRCs are likely not responsive to anti-EGFR monotherapy and can potentially function as a biomarker for CRC progression.

Pubmed ID: 30858928 RIS Download

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Non-profit plasmid repository dedicated to helping scientists around the world share high-quality plasmids. Facilitates archiving and distributing DNA-based research reagents and associated data to scientists worldwide. Repository contains over 65,000 plasmids, including special collections on CRISPR, fluorescent proteins, and ready-to-use viral preparations. There is no cost for scientists to deposit plasmids, which saves time and money associated with shipping plasmids themselves. All plasmids are fully sequenced for validation and sequencing data is openly available. We handle the appropriate Material Transfer Agreements (MTA) with institutions, facilitating open exchange and offering intellectual property and liability protection for depositing scientists. Furthermore, we curate free educational resources for the scientific community including a blog, eBooks, video protocols, and detailed molecular biology resources.

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