COLORECTAL CANCER: Preclinical studies suggest NF1 loss contributes to EGFR inhibitor resistance in RAS/BRAF wild-type disease; this can potentially be ameliorated by combined EGFR-MEK inhibition

Kevin Sovet

June 17, 2020

SCIENTIFIC

COLORECTAL CANCER

Preclinical studies suggest NF1 loss contributes to EGFR inhibitor resistance in RAS/BRAF wild-type disease; this can potentially be ameliorated by combined EGFR-MEK inhibition

 

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

DOI: 10.1158/1541-7786.MCR-19-1201

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 NRAS/KRAS/BRAFV600-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 KRAS/NRAS/BRAFV600-wild-type colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in PTEN 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.

more info: https://mcr.aacrjournals.org/content/18/6/835