Inhibition of HIF1α-Dependent Upregulation of Phospho-l-Plastin Resensitizes Multiple Myeloma Cells to Frontline Therapy

Abstract

The introduction of novel frontline agents in multiple myeloma (MM), like immunomodulatory drugs and proteasome inhibitors, has improved the overall survival of patients. Yet, MM is still not curable, and drug resistance (DR) remains the main challenge. To improve the understanding of DR in MM, we established a resistant cell line (MOLP8/R). The exploration of DR mechanisms yielded an overexpression of HIF1α, due to impaired proteasome activity of MOLP8/R. We show that MOLP8/R, like other tumor cells, overexpressing HIF1α, have an increased resistance to the immune system. By exploring the main target genes regulated by HIF1α, we could not show an overexpression of these targets in MOLP8/R. We, however, show that MOLP8/R cells display a very high overexpression of LCP1 gene (l-Plastin) controlled by HIF1α, and that this overexpression also exists in MM patient samples. The l-Plastin activity is controlled by its phosphorylation in Ser5. We further show that the inhibition of l-Plastin phosphorylation restores the sensitivity of MOLP8/R to immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs). Our results reveal a new target gene of DR, controlled by HIF1α.

A predicted risk score based on the expression of 16 autophagy‑related genes for multiple myeloma survival

“…Hypoxia, a central characteristic for cancer incidence and progression, occurs when most types of cancer are evolving (59)(60)(61)(62)(63)(64). HIF1A is a hypoxia-inducible factor, and constitutive expression of HIF1A in MM indicates that suppression of HIF1A-mediated transcription could become a favorable target for MM (65)(66)(67)(68). For instance, chetomin, an inhibitor of the HIF1A/p300 interaction, can inhibit tumor cell growth of MM (69).…”

LCP1 triggers mTORC2/AKT activity and is pharmacologically targeted by enzastaurin in hypereosinophilia

“…Therefore, Enza is not expected to show clinical benefit in HE patients with ABL translocations. Just recently, high expression of LCP1 was demonstrated in multiple myeloma and its inhibition overcame proteasome inhibitor resistance, again highlighting LCP1 as a worthwhile target in leukemia.…”

Targeting NF-κB Signaling for Multiple Myeloma

“…For instance, radiotherapy represses exosomal release of L-plastin in both the tumor and its niche, producing radiation-induced bystander effects and enhance outcomes [ 113 ]. Inhibition of L-plastin Ser5 phosphorylation re-sensitizes resistant MM cells to IMiDs and proteasome inhibitors [ 114 ]. Collectively, these data suggest that inhibiting L-plastin provides an alternative route to treating MM, specifically in TRAF3 -mutant MM patients.…”