MAP2K1 E203K

This study highlights the aberrant activation of the mitogen-activated protein kinase (MAPK) pathway as another important mechanism of resistance to immunotherapy. This case provides direct clinical evidence that MEK1 E203K is involved in resistance to immune checkpoint inhibitors (ICIs). Furthermore, for the first time, the MEK inhibitor trametinib has shown promising results in treating tumors with this mutation.

The incidence of MAP2K1 mutations was higher in the current study than in previous studies (Garces et al. 2017), though not statistically significant, at 29% (4/14) compared to 16% (8/49; p=0.15).These results highlight the value of stringent tissue microdissection for identifying targetable molecular alterations in RDD and suggest that such approaches may help uncover additional neoplastic drivers and/or mutations implicated in therapeutic resistance.

The NGS panel could successfully detect actionable mutations in liquid biopsies with a high concordance rate and sensitivity. The detection of variants in cfDNA, but not in tDNA, suggests a greater representativeness of the mutational tumor spectrum in samples of liquid biopsies opening perspectives for employing this approach in the routing setting. The NGS assay for liquid biopsy may decrease tissue biopsies and turnaround time for report release, accelerating therapeutic strategies for NSCLC patients.

In addition, two potentially druggable mutations, a MAP2K1 missense mutation (E203K) and a BRAF missense mutation (V600E), were traceable in two undifferentiated (pleomorphic) sarcoma patients (11%; 2/18). Our findings demonstrate that NGS testing is a powerful technology helping to improve diagnostic accuracy and offering some patients the chance for personalized medicine even in a "mutation unlikely" cohort like STS.

Hence, trametinib could dissociate from the active mutants (P124S and E203K) more easily compared with the WT MEK1. In summary, our theoretical results demonstrated that the active mutations may attenuate the inhibitory effects of MEK inhibitor (trametinib) on MEK1, which could be crucial clues for future anti-cancer treatment.