Resolving "Kinks" of Chemotherapy in Melanoma

Abstract

JNCI | Editorials 833 A recent review of our last 35 years of phase 2 clinical trials for metastatic melanoma demonstrates that there has been no statistically significant improvement in 1-year overall survival or 6-month progression-free survival with any intervention tested in multicenter trials to date ( 1 ). An understanding of the basis of failure for these tested agents has generally been lacking, and few of these trials involved laboratory corollary studies of mechanism. Many cell survival and death pathways that are dysregulated in melanoma [reviewed in ( 2 )] and other new pathways that might explain the refractoriness of melanoma to current treatments are under exploration ( 3 ). Melanoma repopulating (stem) cells that are resistant to chemotherapy may also be culpable ( 4 ). Targeting molecules critical for melanoma cell survival in rational combinations may improve the efficacy of chemotherapy, and this is currently being tested in relation to sorafenib. Nuclear factor kappa B (NF B) is the general designation for a family of dimeric complexes of members of the Rel protein family, which are important in melanoma [reviewed in ( 5 , 6 )]. This transcription factor is activated in response to diverse stimuli, including proinfl ammatory cytokines, “nonself” antigens, lymphocyte mitogens, and cellular stress (ultraviolet and ionizing radiation, as well as chemotherapeutic agents). In resting cells, NFB remains cytoplasmic through its association with one of three inhibitory I B proteins (I B , I B , or I B ). It can be activated through at least three different pathways. The canonical pathway exhibits rapid kinetics and is dependent on the stimulation of the inhibitor of I B kinase (IKK), a complex composed of the enzyResolving “Kinks” of Chemotherapy in Melanoma