ERK signaling mediates resistance to immunomodulatory drugs in the bone marrow microenvironment

Immunomodulatory drugs (IMiDs) have markedly improved patient outcome in multiple myeloma (MM); however, resistance to IMiDs commonly underlies relapse of disease. Here, we identify that tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2) knockdown (KD)/knockout (KO) in MM cells mediates IMiD resistance via activation of noncanonical nuclear factor kappa B (NF-kappa B) and extracellular signal-regulated kinase (ERK) signaling. Within MM bone marrow (BM) stromal cell supernatants, TNF-alpha induces proteasomal degradation of TRAF2, noncanonical NF-kappa B, and downstream ERK signaling in MM cells, whereas interleukin-6 directly triggers ERK activation. RNA sequencing of MM patient samples shows nearly universal ERK pathway activation at relapse on lenalidomide maintenance therapy, confirming its clinical relevance. Combination MEK inhibitor treatment restores IMiD sensitivity of TRAF2 KO cells both in vitro and in vivo. Our studies provide the framework for clinical trials of MEK inhibitors to overcome IMiD resistance in the BM microenvironment and improve patient outcome in MM.

Automated summary

Immunomodulatory drugs (IMiDs) have significantly improved patient outcomes in multiple myeloma (MM), but resistance to IMiDs is a common cause of disease relapse. Research has found that TNF receptor-associated factor 2 (TRAF2) knockdown/knockout mediates IMiD resistance in MM cells. Clinical relevance has been confirmed through RNA sequencing of MM patient samples showing ERK pathway activation at relapse on lenalidomide maintenance therapy. Combination MEK inhibitor treatment has been shown to restore IMiD sensitivity in TRAF2 KO cells in both in vitro and in vivo studies.