CRISPR-induced RASGAP deficiencies in colorectal cancer organoids reveal that only loss of NF1 promotes resistance to EGFR inhibition
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Jasmin B. Post1,2, Nizar Hami1,2, Alexander E.E. Mertens1,2, Suraya Elfrink1,2, Johannes L. Bos1,2 and Hugo J.G. Snippert1,2
1Center for Molecular Medicine, Section Molecular Cancer Research, University Medical Center Utrecht, Utrecht, The Netherlands
2Oncode Netherlands, Institute Netherlands, Office Jaarbeurs Innovation Mile, Utrecht, The Netherlands
Hugo J.G. Snippert, email: H.J.G.Snippert@umcutrecht.nl
Keywords: NF1; RASGAP; anti-EGFR therapy resistance; cancer progression; colorectal cancer
Received: December 12, 2018 Accepted: February 01, 2019 Published: February 15, 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.
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