MAP2K1 Mutations in Advanced Colorectal Cancer Predict Poor Response to Anti-EGFR Therapy and to Vertical Targeting of MAPK Pathway

MAP2K1 is a rare oncogenic mutation with clinical and therapeutic implications that have yet to be explored in colorectal cancer. While targeting the MAPK signaling pathway has demonstrated antitumor efficacy in mouse xenograft models, colorectal cancer patients that harbor this mutation are predicted to have a poor response to EGFR inhibitors with or without MEK, BRAF, or ERK inhibition. Our study suggests colorectal cancer patients harboring MAP2K1 mutation may not benefit from anti-EGFR therapy. Background: MAP2K1 mutations, otherwise known as MEK mutations, are rare oncogenic alterations that have been implicated in MAPK pathway activation. The impact of MAP2K1 mutations in colorectal cancer on EGFR antibody response has not been characterized. Patients and Methods: Antitumor activity was assessed in mouse xenograft models with SW48 cell lines harboring MAP2K1 mutation, and protein expression of the RAS signaling pathway was studied by Western blot analysis. We retrospectively identified patients with MAP2K1-mutated metastatic colorectal cancer patients treated at City of Hope Comprehensive Cancer Center between 2015 and 2020 using next-generation sequencing. Patients' tumor characteristics, treatment response, and outcome are described. Additional patients with the MAP2K1 mutation were identified from The Cancer Genome Atlas and Memorial Sloan Kettering Cancer Center oncogenomic databases. Results: Antitumor activity in mouse xenograft models demonstrated efficacy with combination therapy with EGFR and MEK inhibition with either BRAF or ERK inhibitors. Five patients treated at City of Hope between 2015 and 2020 harbored a MAP2K1 mutation at a frequency of 1%. APC and TP53 were common coalterations. All disease was RAS and BRAF wild type, except 1 case that harbored a concurrent KRAS mutation. Four RAS/BRAF wild-type MAP2K1-mutated patients was treated with anti-EGFR, anti-EGFR thorn MEK and BRAF inhibitors, and anti-EGFR thorn ERK inhibitors. All 4 patients experienced disease progression. Conclusion: MAP2K1 mutation in colorectal cancer is associated with poor response to EGFR inhibition. EGFR inhibition with or without MEK, BRAF, or ERK inhibitors did not result in any clinical benefit in our limited experience. (C) 2020 Elsevier Inc. All rights reserved.