A case of class 3 MEK1 mutated metastatic colorectal cancer with a non-durable tumor marker response to MEK and ERK inhibitors

Class 3 MEK1 mutations disrupt the negative regulatory helix region of MEK1 and drive constitutive activation of both pMEK and pERK that is independent of RAF and of MEK phosphorylation. Targeting MEK with trametinib resulted in mixed clinical responses in class 3 MEK1 mutated Langerhans cell histiocytosis (LCH). The ERK inhibitor, ulixertinib, demonstrated limited anti-tumor activity in non-characterized MEK1 mutated solid tumors, with 2 out 4 patients experiencing stable disease (SD). Here, we present the case of a 52-year-old female with metastatic colon cancer harboring a MEK1E102_I103del (class 3 mutation) who progressed on standard chemotherapy and showed no response to the MEK inhibitor trametinib, the ERK inhibitor ulixertinib, and the combination of ulixertinib and the anti-EGFR antibody panitumumab. Despite progressive disease (PD), the patient exhibited a steep but short-lived tumor marker response to MEK and ERK inhibition, suggesting the emergence of early mechanisms of resistance to MAPK pathway inhibition. This report presents the first case in the literature investigating a MEK inhibitor and an ERK inhibitor (alone and in combination with anti-EGFR therapy) in metastatic colorectal cancer harboring a class 3 MEK1 mutation (E102-I103 deletion).