Concurrent MEK2 Mutation and BRAF Amplification Confer Resistance to BRAF and MEK Inhibitors in Melanoma

Abstract

Summary Although BRAF and MEK inhibitors have proven clinical benefits in melanoma, most patients develop resistance. We report a de novo MEK2-Q60P mutation and BRAF gain in a melanoma from a patient who progressed on the MEK inhibitor trametinib and did not respond to the BRAF inhibitor dabrafenib. We also identified the same MEK2-Q60P mutation along with BRAF amplification in a xenograft tumor derived from a second melanoma patient resistant to the combination of dabrafenib and trametinib. Melanoma cells chronically exposed to trametinib acquired concurrent MEK2-Q60P mutation and BRAF-V600E amplification, which conferred resistance to MEK and BRAF inhibitors. The resistant cells had sustained MAPK activation and persistent phosphorylation of S6K. A triple combination of dabrafenib, trametinib, and the PI3K/mTOR inhibitor GSK2126458 led to sustained tumor growth inhibition. Hence, concurrent genetic events that sustain MAPK signaling can underlie resistance to both BRAF and MEK inhibitors, requiring novel therapeutic strategies to overcome it.

Increased MAPK reactivation in early resistance to dabrafenib/trametinib combination therapy of BRAF-mutant metastatic melanoma

“…Previous reports indicating that MEK2, rather than MEK1, can escape inhibition by the allosteric MEK inhibitor AZD6244 (ref. 37) and that MEK2 is the more potent ERK activator 38,39 are consistent with our data and recent reports of MEK2 mutations in CombiDT-resistant melanomas 16,17 . Current data suggest that ERK activity is gradually restored in the presence of BRAF and MEK inhibitors via receptor tyrosine kinase reprogramming driven by the loss of suppressive feedback regulation 11,37,40 .…”

“…This finding was unexpected given first the substantially lower incidence of BRAF amplification in tumours progressing on BRAF inhibitor monotherapy (18/140 ¼ 13%) [7][8][9] , and second, preclinical studies showing that overexpression of BRAF in sensitive melanoma cells confers resistance to MEK inhibitor monotherapy, but they remain sensitive to combined BRAF and MEK inhibition 10 . We therefore examined the extent of BRAF amplification in several cohorts [7][8][9]17 , and, although the numbers of tumours available for analyses were small, we found a significant increase in the BRAF Prog to pre-treatment copy number ratio in CombiDT-resistant tumours compared with tumours progressing on BRAF inhibitor monotherapy (P ¼ 0.04; Fig. 2c).…”

Targeting cancer with kinase inhibitors

“…These results are consistent with preclinical studies showing that sustained >80% pathway inhibition and relief of ERK1-and ERK2-dependent (encoded by MAPK3 and MAPK1, respectively) feedback results in enhanced antitumor efficacy (77)(78)(79). Furthermore, preclinical and clinical evidence suggests that additional MAPK pathway alterations, including activating mutations in MEK1 and MEK2, confer resistance to combined BRAF and MEK1/2 inhibition (80)(81)(82). The emergence of these additional mechanisms of resistance supports the development of novel inhibitors of multiple upstream and downstream kinase components for the next generation of combination therapy treatments.…”

Many are better than one - Next Generation Multi-Variate Biomarkers for Precision Oncology

“…While response rates in this sub-population are impressive, approximately half do not respond, and the majority of the responders will eventually acquire resistance [10] . Many genetic mechanisms of resistance have been cataloged [11] , including NF1 loss-of-function mutations [12] , NRAS activating mutations, BRAFV600E splicing variant, MEK1 mutation, COT expression, BRAFV600E amplification, BRAF G469L mutation [13] , concurrent MEK2 mutation and BRAF amplification [14] , AEBP1 upregulation [15] , MAP2K2 and MITF genomic alterations [16] and MEK2 Q60P mutation [17] , all of which result in reactivation of MAPK signaling, as well as the activation of parallel survival pathways such IGF1R/PI3K-AKT signaling [18] .…”