Abstract
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.
Highlights
Colorectal cancer (CRC) is one of the most common cancers and the third leading cause of worldwide cancer deaths (IARC)
Treatment with epidermal growth factor receptor (EGFR) targeting monoclonal antibodies (moAbs) resulted in initial response rates of 10–20% in metastatic CRC (mCRC) patients [1], but it soon became clear that tumors with activating mutations in KRAS showed resistance to EGFR inhibition [2, 3, 6]
Data analysis of patients with lung adenocarcinoma and melanoma show that of all RASGAPs only inactivating mutations in NF1 tend to occur in a mutually exclusive manner with activating hotspot mutations in KRAS, NRAS and BRAF
Summary
Colorectal cancer (CRC) is one of the most common cancers and the third leading cause of worldwide cancer deaths (IARC). The use of monoclonal antibodies (moAbs) targeting the epidermal growth factor receptor (EGFR), such as cetuximab and panitumumab, together with chemotherapy has shown a clinical benefit for the treatment of patients with metastatic CRC (mCRC) [1,2,3]. The binding of these antibodies to the extracellular domain of the EGFR inhibits downstream activation of the RASMEK-ERK signaling pathway, thereby inhibiting cell proliferation and survival [4, 5]. These patients are being excluded from EGFR targeted therapy [7, 8]
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