MEK inhibitor resistance by ERK5 in NRAS-driven melanoma

What is it about?

Targeted therapies that inhibit the RAS/RAF/MEK/ERK MAPK pathway are important treatment options for several tumor cell types characterized by deregulated MEK1/2/ ERK1/2 activation. However, such MAPK- inhibiting (MAPKi) therapies are hampered by the frequent occurrence of intrinsic or therapy-induced resistance. This is particularly true for tumors driven by oncogenic mutation of the RAS genes, including NRAS-mutant melanoma, where neither available inhibitors of oncogenic BRAF V600 (BRAFi) nor MEK1/2-specifc inhibitors (MEKi) are clinically effective. The stress- and growth factor-activated MEK5/ERK5 MAPK pathway has recently emerged as an important pathway mediating therapeutic resistance to MAPKi in several tumors characterized by constitutive activation of the ERK1/2 pathway. Preclinical studies in a variety of different RAS-mutant cancer cell types, including our own in NRAS-mutant melanoma, have demonstrated that combined treatment with MEKi and pharmacological inhibitors targeting ERK5 (ERK5i) dramatically improves MEKi-dependent tumor suppression in vitro and in xenotransplantation models in vivo. However, the underlying mechanism for this dramatically increased tumor-suppressive effect by ERK5 co-inhibition is still largely unclear. Our study now reveals how inhibition of MEK1/2 and ERK5 induces a multilayered, robust cell cycle arrest in melanoma and puts forward an alternative therapy option for NRAS-mutant melanoma.

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Why is it important?

Our data suggest Cyclin D/CDK4 dependency as a major vulnerability of NRAS-mutant melanoma that could effectively be targeted by combined MAPKi/ERK5i. Given the robust and durable cell cycle arrest of combined MEKi/ERK5i, we propose that particularly NRAS-mutant melanoma patients ineligible for or resistant to immune checkpoint blockade may benefit from MEKi/ERK5i combination therapies.