Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma

Abstract

Acquired resistance to BRAF inhibitors often involves MAPK re-activation, yet the MEK inhibitor trametinib showed minimal clinical activity in melanoma patients that had progressed on BRAF-inhibitor therapy. Selective ERK inhibitors have been proposed as alternative salvage therapies. We show that ERK inhibition is more potent than MEK inhibition at suppressing MAPK activity and inhibiting the proliferation of multiple BRAF inhibitor resistant melanoma cell models. Nevertheless, melanoma cells often failed to undergo apoptosis in response to ERK inhibition, because the relief of ERK-dependent negative feedback activated RAS and PI3K signalling. Consequently, the combination of ERK and PI3K/mTOR inhibition was effective at promoting cell death in all resistant melanoma cell models, and was substantially more potent than the MEK/PI3K/mTOR inhibitor combination. Our data indicate that a broader targeting strategy concurrently inhibiting ERK, rather than MEK, and PI3K/mTOR may circumvent BRAF inhibitor resistance, and should be considered during the clinical development of ERK inhibitors.

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

“…Analysis of patient-derived and in vitro-generated dabrafenib-resistant melanoma cell lines expressing endogenous BRAF-splice variants lacking exons 2-8, 2-10 and 4-10 (ref. 14) confirmed that these cells were resistant to dabrafenib monotherapy but retained sensitivity to singleagent trametinib (Fig. 4a).…”

“…Consequently, although the sole activation of PI3K activity may not be sufficient to confer CombiDT resistance, we predict that PI3K activity modulates tumour responses to MAPK inhibitors and contributes to early resistance, and that combination MAPK and PI3K/AKT inhibition may be best administered upfront to delay the emergence of resistance 35 . Preclinical data have confirmed that PI3K activation (via NRAS mutations and receptor tyrosine kinase activation) diminished melanoma cell responses to combination BRAF and MEK inhibitors 14 . The hotspot RAC P29S mutation also confers resistance to RAF and MEK inhibitors 26 .…”

“…The predominance of MAPK reactivation in tumours progressing on CombiDT is unexpected and carries important implications for future clinical trial design strategies in these patients. The abundance of BRAF amplifications is of particular note as ERK inhibitors are active in the context of BRAF copy number gains 34 , including in models resistant to combined BRAF and MEK inhibition 14 . Furthermore, these data suggest that, in unselected patients with CombiDT failure, drug combinations involving PI3K/AKT inhibition (for example, NCT 01902173; ref.…”

“…Given that many BRAF inhibitor resistance mechanisms are sensitive to MEK inhibition, alone or in combination with BRAF inhibition 7,10,14,15 , MAPK-independent mechanisms of resistance might be anticipated to predominate in melanomas treated with combined BRAF/MEK inhibition.…”

“…The MEK2 Q60P mutation and BRAF amplification have been shown to confer resistance to combined BRAF and MEK inhibition in preclinical models 16 . BRAF-splice variants, however, remain sensitive to MEK inhibition 7,12,14 , thus the contribution of BRAF ex2-10D in combination BRAF/MEK resistance remains unclear.…”