Nrf2: not “lost in translation”

Multiple myeloma (MM) is a clonal plasma cell malignancy which is frequently diagnosed in patients over 65 years of age. Because of an aging population, the incidence of MM has increased nearly 1 percent annually since 1975 and it is anticipated that the number of cases will nearly double by 2034 [1]. The introduction of novel agents such as the proteasome inhibitor bortezomib (BTZ) has significantly improved overall survival of patients with MM during the past decade. Therapeutic efficacy is related to the exquisite dependence of MM cells on proteasomal degradation of unfolded proteins to maintain proteostasis. However, progression towards BTZ-refractory disease occurs in the majority of MM patients. Unfortunately, once MM patients become refractory to BTZ, their median overall survival has been reported to be less than 1 year [2]. Moreover, in a pivotal phase 2 study with the secondgeneration proteasome inhibitor carfilzomib (CFZ), less than a 25% response rate was achieved in BTZ-treated patients who had relapsed [3]. These results indicate that the majority of MM cells that became resistant to BTZ were also resistant to CFZ. Clearly, to extend the life expectancy of patients with MM, it is essential to elucidate the underlying mechanisms of acquired proteasome inhibitor resistance. Toward this goal, we have endeavored to establish clinically relevant CFZ-resistant sublines of patientderived MM cell lines. We have demonstrated that diverse adaptive mechanisms confer CFZ resistance in these MM cell line models, including increased prosurvival autophagy (as a compensatory mechanism to counter proteasome insufficiency), antioxidant defense and expression of the P-glycoprotein efflux pump [4-6]. In our most recent publication, we described the establishment of a new CFZ-resistant derivative of the LP-1 MM cell line, LP-1/Cfz, in which CFZ resistance involved post-transcriptional activation of nuclear factor-erythroid 2 (NF-E2)-related factor 2 (Nrf2; gene symbol NFE2L2) [6]. Under physiological conditions, transcription factor Nrf2 maintains cellular redox homeostasis [7]. Congruent with Nrf2 activation, LP-1/Cfz cells had decreased levels of reactive oxygen species as well as elevated levels of fatty acid oxidation and prosurvival autophagy. Accordingly, genetic and pharmacologic inhibition of Nrf2, disruption of redox Editorial