Abstract 2140: Dual Wnt and EGFR-MAPK dependency of BRAFV600E-mutant colorectal cancer

Aberrant Wnt pathway activation due to inactivating mutations in the gene encoding RNF43 (an E3 ubiquitin ligase that promotes degradation of the Wnt receptors Frizzled and LRP6) may contribute to the unresponsiveness of BRAF V600E -mutant colorectal cancer (CRC) to BRAF inhibitors. Analysis of The Cancer Genome Atlas (TCGA) CRC data set reveals a striking co-occurrence of the BRAF V600E mutation and truncating mutations in RNF43. RNF43 mutations are likely to be functionally significant, as RNF43 mutations and mutations in the β-catenin destruction complex component APC are almost completely mutually exclusive. The vast majority of BRAF V600E ;RNF43-mutant CRCs are hypermutable [microsatellite instability (MSI)-high phenotype]. The mismatch repair deficiency in these tumors may directly contribute to RNF43 mutagenesis, as RNF43 mutations tend to be small insertions/deletions in homopolymeric tracts. To determine if RNF43 mutations confer Wnt dependency in BRAF V600E -mutant CRC, we treated three BRAF V600E ;RNF43-mutant CRC patient-derived xenograft (PDX) models with the porcupine inhibitor WNT974 (formerly LGK974), which blocks the palmitoylation and secretion of Wnt ligands. Single agent WNT974 anti-tumor activity was observed in 2/3 PDX models, and correlated with decreased tumor cell proliferation and mucinous differentiation. Single agent anti-tumor activity with the BRAF inhibitor LGX818 was also observed in 2/3 PDX models. No single agent anti-tumor activity was observed with the EGFR inhibitor cetuximab. The double combinations of WNT974+LGX818 and LGX818+cetuximab, and the triple combination of WNT974+LGX818+cetuximab were efficacious in all three BRAF V600E ;RNF43-mutant CRC PDX models. In summary, the Wnt pathway and the EGFR-MAPK pathway may jointly promote tumorigenesis of BRAF V600E -mutant CRC, providing a strong rationale to treat patients with BRAF V600E -mutant CRCs harboring upstream Wnt pathway mutations with combinations of WNT974, LGX818 and/or cetuximab. Citation Format: Youzhen Wang, Michael Palmer, Savina Jaeger, Linda Bagdasarian, Shumei Qiu, Steve Woolfenden, Ronald Meyer, Guizhi Yang, John Green, Shifeng Pan, Jun Liu, Hui Gao, Z. Alexander Cao, Andrea Myers, Margaret E. McLaughlin. Dual Wnt and EGFR-MAPK dependency of BRAF V600E -mutant colorectal cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2140. doi:10.1158/1538-7445.AM2015-2140