Inactivation of NF1 promotes resistance to EGFR inhibition in KRAS/NRAS/BRAFV600-wildtype colorectal cancer

Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in NRAS/KRAS/BRAFV600-wildtype colorectal cancer (CRC) cells. Reduced NF1 expression permitted sustained signalling through the MAPK (mitogen-activated protein kinase) pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition lead to synergistic antiproliferative activity. Human KRAS/NRAS/BRAFV600-wildtype colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Co-occurring loss-of-function mutations in PTEN were associated with resistance to dual EGFR/MEK inhibition but co-treatment with a PI3 kinase inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single agent anti-EGFR therapy in CRC and may direct potential combination strategies. Implications: This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in CRC patients with KRAS/NRAS/BRAFV600-wildtype tumours is warranted.