Increased MAPK reactivation in early resistance to dabrafenib/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 6 months. Treatment options for these patients remain limited. Here we analyse 20 BRAF V600 -mutant melanoma metastases derived from 10 patients treated with the combination of dabrafenib and trametinib for resistance mechanisms and genetic correlates of response. Resistance mechanisms are identified in 9/11 progressing tumours and MAPK reactivation occurred in 9/10 tumours, commonly via BRAF amplification and mutations activating NRAS and MEK2. Our data confirming that MEK2 C125S , but not the synonymous MEK1 C121S protein, confers resistance to combination therapy highlight the functional differences between these kinases and the preponderance of MEK2 mutations in combination therapy-resistant melanomas. Exome sequencing did not identify additional progression-specific resistance candidates. Nevertheless, most melanomas carried additional oncogenic mutations at baseline (for example, RAC1 and AKT3) that activate the MAPK and PI3K pathways and are thus predicted to diminish response to MAPK inhibitors.

Targeted agents and immunotherapies: optimizing outcomes in melanoma

“…In the largest studies to date 20,[116][117][118] , involving 132 samples obtained at the time of clinical resistance, one or more genomic causes of resistance were identified in 58% of patients: NRAS/KRAS mutation in 20%, BRAF splice vari ants in 16%, BRAF amplification in 13%, MEK1/2 mutation in 7%, and non-MAPK-pathway alterations in 11%. Similar resistance mechanisms have been described with combined BRAF-MEK inhibition 119,120 . These genomic data have been confirmed in other studies; however, a large fraction of BRAF-MEK inhibitor resistance might also be driven through non-genomic or immune mechanisms of tumour escape 121 .…”

TERT promoter mutations in melanoma survival

“…2 HR adjusted for BRAF/NRAS mutations, rs2853669, age at diagnosis and tumor stage. 3 HR adjusted for BRAF/NRAS mutations, age at diagnosis and tumor stage.…”

“…2 HR adjusted for BRAF/NRAS mutations, rs2853669, age at diagnosis, tumor stage and treatment. 3 HR adjusted for BRAF/NRAS mutations, age at diagnosis, tumor stage and treatment. 4 HR not calculable as no events were recorded for patients without mutations and for patients with only TERT mutations.…”

“…2 Despite increased possibilities, with range of treatments including targeted and immunotherapies, of eliciting stable responses in patients with metastatic melanoma, the long-term prospectus in terms of treatment response is confined to disease management. 3 The identification of patients at risk of developing advanced disease at an early stage through use of somatic mutations as molecular biomarkers remains a valid medical issue.The melanoma genome is characterized by one of the highest prevalence of somatic mutations, and the mutational pattern depicts characteristic ultraviolet signature. 4 Besides recurrent mutations in TERT promoter, BRAF/NRAS, CDKN2A, NF1, PTEN and others genes, various sequencing initiatives have identified mutations in a number of other genes including GRIN2A, RAC1, BCL2L12, STK19, FBXW7 and RPS27.…”

Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)

“…Genetic mechanisms of acquired resistance to single-agent BRAF inhibition have been intensely studied; some examples of identified resistance mechanisms include splice variants of BRAF (16), BRAF V600E amplification (17), MEK mutations (18), NRAS mutations, and RTK activation (19,20). Resistance mechanisms in the setting of BRAF/MEK inhibitor combination therapy are beginning to emerge and mirror that of BRAF single-agent resistance (21,22). These genetic events all share the ability to reactivate ERK signaling.…”