Targeting metabolism to overcome cancer drug resistance: A promising therapeutic strategy for diffuse large B cell lymphoma.

Cancer cell metabolism including aerobic glycolysis, amino acid and fatty acid metabolism, has been extensively studied. Metabolic reprogramming is a major hallmark of cancer, which promotes cancer cell proliferation, progression and metastasis, as well as provokes resistance to chemotherapeutic drugs. Several signal transduction pathways, such as BCR, MEK/ERK, Notch, NF-κB and PI3K/AKT/mTOR, regulate tumor metabolism, hence promoting tumor cell growth, proliferation and progression. Therefore, targeting metabolic enzymes, metabolites or their signal transduction pathways may constitute a promising therapeutic strategy to enhance cancer treatment efficacy. Diffuse large B-cell lymphoma (DLBCL) is the most aggressive form of non-Hodgkin lymphoma (NHL), and one-third of DLBCL patients suffer from relapsed/refractory disease after chemotherapy. The mechanisms underlying drug resistance are complex, including target gene mutations, metabolic reprogramming, aberrant signal transduction pathways, enhanced drug efflux via overexpression of multidrug efflux transporters like P-glycoprotein, upregulation of anti-apoptotic proteins, drug sequestration and enhanced DND repair. This review delineates the distinct metabolic reprogramming patterns and the association between metabolism and anticancer drug resistance in DLBCL as well as the emerging strategies to surmount chemoresistance in DLBCL.

Metabolic Reprogramming Induces Immune Cell Dysfunction in the Tumor Microenvironment of Multiple Myeloma.

Tumor cells rewire metabolism to meet their increased nutritional demands, allowing the maintenance of tumor survival, proliferation, and expansion. Enhancement of glycolysis and glutaminolysis is identified in most, if not all cancers, including multiple myeloma (MM), which interacts with a hypoxic, acidic, and nutritionally deficient tumor microenvironment (TME). In this review, we discuss the metabolic changes including generation, depletion or accumulation of metabolites and signaling pathways, as well as their relationship with the TME in MM cells. Moreover, we describe the crosstalk among metabolism, TME, and changing function of immune cells during cancer progression. The overlapping metabolic phenotype between MM and immune cells is discussed. In this sense, targeting metabolism of MM cells is a promising therapeutic approach. We propose that it is important to define the metabolic signatures that may regulate the function of immune cells in TME in order to improve the response to immunotherapy.