Inactivation of <i>NF1</i> Promotes Resistance to EGFR Inhibition in <i>KRAS/NRAS/BRAFV600</i> -Wild-Type Colorectal Cancer

Abstract

Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in <i>NRAS/KRAS/BRAF^V600</i> -wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human <i>KRAS/NRAS/BRAF^V600</i> -wild-type colorectal cancer cell lines with <i>NF1</i> mutations displayed reduced <i>NF1</i> mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in <i>PTEN</i> were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K 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 colorectal cancer and may direct potential combination strategies. IMPLICATIONS: This study suggests that further clinical validation of <i>NF1</i> status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with <i>KRAS/NRAS/BRAF^V600</i> -wild-type tumors is warranted.