Predominance of MAPK reactivation in early resistance to debrafenib/trametinib combination therapy of BRAF mutant metastatic melanoma.

ABSTRACT: One third of BRAF-mutant metastatic melanoma patients treated with combined BRAF and MEK inhibition progress within six months. Treatment options for these patients remain limited. Here we analyse twenty BRAFV600 mutant melanoma metastases derived from 10 patients treated with the combination of debrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumors and MAPK reactivation occurred in 9/10 tumors, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2C125S, but not the synonymous MEK1C121S protein confers resistance to combination therapy, highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combinatio

ORGANISM(S): Homo sapiens

SUBMITTER: Gulietta Pupo 

PROVIDER: E-GEOD-61992 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress