Growth factors and antiapoptotic signaling pathways in multiple myeloma

Abstract

Failure of myeloma cells to undergo apoptosis plays an important role in the accumulation of myeloma cells within the bone marrow (BM). Moreover, inhibition of drug-induced apoptosis has been indicated as a major contributor of drug resistance in myeloma. The BM microenvironment promotes survival and blocks the apoptotic effects of various cytotoxic agents through the production of cytokines as well as through direct physical interactions. Several antiapoptotic proteins and antiapoptotic signaling cascades have been identified that contribute to the antiapoptotic phenotype of the myeloma cell. In this review, we discuss mechanisms that result in enhanced survival and drug resistance of myeloma cells. Insight into these mechanisms is essential to make progress in the therapy of myeloma.

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting

“…The best characterized myeloma growth factor is the cytokine interleukin-6 (IL-6) [9]. However, an increasing number of cytokines, chemokines and cell-to-cell contacts provided by the BM has been found to activate a pleiotropic cascade of proliferative/antiapoptotic signaling pathways including JAK/STAT, PI3K/AKT, RAS/ERK and their downstream components [10].…”

“…Since failure to undergo apoptosis has been suggested to play a main role in MM cell accumulation within the BM as well as in drug resistance [9], blocking both intrinsic and BM microenvironment-driven signaling could be required to induce tumor cell death. Multi-targeting approaches represent thereby an attractive therapeutic strategy for MM.…”

Monoclonal antibody-based therapy as a new treatment strategy in multiple myeloma

“…55,56 Insulin-like growth factor-1 receptor IGF-1 is another important growth and survival factor for myeloma cells, through activation of PI3K/Akt and Ras/MAPK signaling pathways. 6 Importantly, IGF-1 also protects myeloma cells against anticancer drugs including bortezomib. 57 IGF-1 receptor (IGF-1R) gene is not expressed by normal B cells or plasma cells, whereas expression of this gene is observed in myeloma cells from 31 to 50% of untreated patients.…”

“…6 IL-6 also protects against various antimyeloma agents including dexamethasone. 6,39 Murine anti-IL-6mAbs have been used in the treatment of myeloma patients, without major side effects and with some evidence of clinical activity. 40,41 However, in a randomized trial performed by the IFM group, addition of the murine anti-IL6mAb, B-E8, to a tandem transplantation program had no effect on overall or event-free survival.…”

“…6 Adhesion is mediated by cellular receptors and results in the activation of important signaling cascades in both the myeloma cell and stromal cell, leading to protection against apoptosis and increased production of several myeloma growth factors, including interleukin-6 (IL-6), insulin growth factor-1 (IGF-1) and vascular endothelial growth factor (VEGF). Over the past few years, various mAbs targeting adhesion molecules present on myeloma cells showed great promise in both preclinical and early clinical studies.…”