In September 2019, a 62-year-old man was diagnosed with RAS and BRAF WT, ERBB2 not-amplified, MSS, right-sided mCRC with synchronous liver and bone metastases. Initially, the patient underwent FOLFOX first-line therapy for 12 cycles achieving PR, followed by a therapeutic holiday due to an occurring, non-treatment related intracranial hemorrhagic event. Following systemic PD, the patient received palliative bone RT and FOLFIRI as second line therapy, with further PD. Given the absence of available clinical trials and according to the molecular status, the patient started third line panitumumab monotherapy in October 2020. After 3 cycles, due to worsening clinical conditions, we performed a CT scan demonstrating dimensional and numerical PD. At this stage, aiming to expand druggable therapeutic targets, a FoundationOne CDx NGS panel was performed on archival FFPE tissue from the primary tumor biopsy undergone at baseline. The case was presented at MTB: although no druggable targets were retrieved, a tumor somatic MAP2K1 N57K mutation was found, with a 14.7% VAF, thus potentially entailing anti-EGFR resistance. This was confirmed by LB through ddPCR showing a 0.51% MAF. Subsequently, the patient was treated with FOLFOX reintroduction achieving PD as best response, and then regorafenib with SD. In July 2021, further palliative RT was provided for worsening gonalgia secondary to a knee bone metastasis. However, the patient died on August 20th 2021 ( Figure 1  and  Table 1 ).