Drug resistance in multiple myeloma: latest findings and new concepts on molecular mechanisms

Abstract

In the era of new and mostly effective therapeutic protocols, multiple myeloma still tends to be a hard-to-treat hematologic cancer. This hallmark of the disease is in fact a sequel to drug resistant phenotypes persisting initially or emerging in the course of treatment. Furthermore, the heterogeneous nature of multiple myeloma makes treating patients with the same drug challenging because finding a drugable oncogenic process common to all patients is not yet feasible, while our current knowledge of genetic/epigenetic basis of multiple myeloma pathogenesis is outstanding. Nonetheless, bone marrow microenvironment components are well known as playing critical roles in myeloma tumor cell survival and environment-mediated drug resistance happening most possibly in all myeloma patients. Generally speaking, however; real mechanisms underlying drug resistance in multiple myeloma are not completely understood. The present review will discuss the latest findings and concepts in this regard. It reviews the association of important chromosomal translocations, oncogenes (e.g. TP53) mutations and deranged signaling pathways (e.g. NFκB) with drug response in clinical and experimental investigations. It will also highlight how bone marrow microenvironment signals (Wnt, Notch) and myeloma cancer stem cells could contribute to drug resistance in multiple myeloma.

Figure 1. SFM-DR and CAM-DR work usually together within the bone marrow environment

Adhesion of MM cells to BMSCs and FN through integrin molecules triggers a variety of signaling pathways (including Ras/MAPK, PI3K/Akt, NFκB, Notch, Wnt, HSPs) involved in cell proliferation, anti-apoptosis, DR and cytokine secretion (IL-6), and also upregulation of anti-apoptotic BCL-2 family members BCL-2, MCL-1 or BCL-XL. The above adhesion induces secretion of several cytokines (IL-6, VEGF, HGF, IGF-1, SDF-1α, TNF-α, MCP-1) by BMSCs leading to triggering most of above pathways and induction of resistance to apoptosis and drugs in MM cells (paracrine). IL-6 can also stimulate MM cells in an autocrine manner, although this system has been shown for some other cytokines as well. Furthermore, most above cytokines may also be secreted by osteoclasts, endothelial cells and macrophages during their direct or indirect interactions with MM cells leading to triggering of above functional responses in latter cells.