Clinical and Biologic Relevance of Fanconi Anemia-BRCA Pathway in Myeloma

In this paper, Yarde and colleagues from H. Lee Moffitt Cancer Center provide for the first time evidence that NF-κB subunits RelB/p50 transcriptionally activate the Fanconi anemia/BRCA (FA/BRCA) pathway in myeloma. Their previous studies have implicated activation of this pathway mediating melphalan resistance in myeloma; importantly, in this study, they demonstrated that NF-κB inhibition by siRNA, IkB kinase blockade, or the proteasome inhibitor bortezomib decreased FA/BRCA gene expression in myeloma, thereby decreasing DNA damage repair and enhancing tumor cell sensitivity to melphalan. These studies therefore suggest that targeting FA/BRCA may enhance sensitivity or overcome drug resistance in myeloma.

The majority of multiple myeloma cells are initially sensitive to DNA damaging agents, including alkylating agents and anthracyclines, but inevitably acquire resistance correlating with the level of clinical exposure. Moreover, this drug-resistant phenotype is associated with progression of disease. Importantly, in preclinical studies and clinical trials, the proteasome inhibitor bortezomib can overcome resistance to conventional agents, including DNA-damaging agents. A randomized trial in relapsed refractory myeloma showed increased rate and extent of response, as well as prolonged progression-free and overall survival, in a patient cohort treated with pegylated liposomal doxorubicin and bortezomib versus bortezomib alone. Most recently, another landmark randomized trial in newly diagnosed elderly patients with myeloma further confirmed that adding bortezomib to DNA-damaging agent melphalan with prednisone (MP) markedly increased both response and survival compared to MP alone. The mechanism whereby bortezomib sensitizes or overcomes resistance to alkylating agents, however, was not previously defined.

The original premise for the use of bortezomib in myeloma was inhibition of NF-κB activation, which is implicated in tumor cell survival and drug resistance, modulation of myeloma cell adhesion to extracellular matrix proteins and bone marrow stromal cells, and secretion of cytokines in the bone marrow milieu. Bortezomib clearly has multiple activities other than NF-κB activation on the one hand, and the biologic phenotype of inhibition of NF-κB is not fully defined on the other. Moreover, bortezomib may even activate NF-κB in some myeloma cells, depending on whether canonical or non-canonical activation mechanisms are present. Prior studies from Dalton and colleagues have implicated the FA/BRCA pathway in conferring melphalan resistance, and the current elegant study provides convincing evidence that constitutive activation of NF-κB in myeloma results in activation of this pathway both in myeloma cell lines and patient cells. Most importantly, either selective knockdown of NF-κB p50/RelB or bortezomib can sensitize or overcome melphalan resistance. This study not only delineates another mechanism of melphalan resistance and strategy for overcoming it with proteasome inhibitors preclinically, but it also has other important implications. Since melphalan remains a mainstay of treatment for newly diagnosed myeloma, at low doses with prednisone in older patients and at high doses in candidates for stem cell transplantation, this study lends further support for incorporation of bortezomib in front-line therapy. It also suggests the therapeutic potential of developing therapies selectively targeting the FA/BRCA pathway to overcome drug resistance, thereby improving patient outcome.