Inactivation of NF1 Promotes Resistance to EGFR Inhibition in KRAS/NRAS/BRAFV600-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 NRAS/KRAS/BRAF V600-wildtype 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/BRAF V600-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. 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. Implications: This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with KRAS/NRAS/ BRAF V600-wild-type tumors is warranted.

Mutational profiles of metastatic colorectal cancer treated with FOLFIRI plus cetuximab or bevacizumab before and after secondary resection (AIO KRK 0306; FIRE‐3)

“…Additional RAS mutations with low mutated allele frequency were described as a mechanism of resistance by clonal selection 19,20 . Beyond RAS , inactivation of NF1 and gain of CNA in GNAS and SRC , respectively, were observed after resection of metastases in two patients, for which intrinsic resistance towards cetuximab has been reported previously 21‐23 . Conversely, 6 of 9 patients who underwent secondary resection did not display any known markers of resistance by NGS.…”

Knowledge Graph-based Recommendation Framework Identifies Novel Drivers of Resistance in EGFR mutant Non-small Cell Lung Cancer

“…Our expectation was that deregulation of PTEN, NF1 and KCTD5 should mediate a stable resistance phenotype, since these genes were shown to negatively regulate MAPK or PI3K/AKT signalling [43][44][45] -known drivers of EGFR TKI resistance. To test this hypothesis we established a flow cytometry based long-term competition assay (Figure 5, B).…”

The role of mutations in <i>NF1</i> gene in sporadic carcinogenesis

“…Роль мутаций в NF1 в развитии химиорезистентности была доказана в ходе экспериментов. На линиях клеток колоректального рака показано, что мутации в этом гене вызывают резистентность к терапии ингибиторами EGFR [19] [20].…”

“…Трансляция / Translation противоопухолевого ответа CD8+ Т-клеток с помощью анти-PD-L1 (лиганда рецептора запрограммированной клеточной гибели 1) [57], который был предложен для лечения нейрофибром при НФ1 [58]. В ходе эксперимента на линиях клеток колоректального рака устойчивость к ингибиторам EGFR преодолевалась с помощью совместного применения ингибиторов EGFR и ингибитора MEK селуметиниба [19]. Чувствительность нейробластомы к ретиноевой кислоте также восстанавливалась при использовании ингибиторов МЕК [15].…”

“…Исследование особенностей патогенеза НФ1 может стать основой для разработки перспективных способов лечения спорадических ЗНО, в развитии которых участвуют мутации в NF1. Это связано с тем, что данные опухоли отличаются химиорезистентностью к препаратам, эффективным при терапии опухолей, в которых не обнаруживаются мутации в NF1 [15][16][17][18][19][20]. Логично рассмотреть взаимосвязь специфических клинических проявлений НФ1 и роли соматических мутаций в развитии спорадических ЗНО (рис.…”