E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271

Abstract

Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.

Functional Blockade of E-Selectin in Tumor-Associated Vessels Enhances Anti-Tumor Effect of Doxorubicin in Breast Cancer

“…Thus, it is critical to establish a stratgegy for patient stratification and treatment scheduling (e.g., duration and administration sequence with chemotherapy). Given the pivotal role of E-selectin as a mediator of tissue migration and its spatiotemporally limited expression on the luminal surface of inflamed vessels, different chemical entities of antagonistic ligands have been developed [21,[34][35][36][37][38].…”

Targeting Aberrant Sialylation to Treat Cancer

“…Similarly, ST3GAL4 is also upregulated in cancer, and is associated with poor prognosis; metastasis and the synthesis of Sialyl Lewix X (sLe X ) in gastric carcinoma [18,35]. ST3GAL6 is also linked to the synthesis of sLe X and the generation of E-selectin ligands [36,37]. Recently, ST3GAL6 was found to be critical to bone…”

“…Similarly, ST3GAL4 is also upregulated in cancer, and is associated with poor prognosis; metastasis and the synthesis of Sialyl Lewix X (sLe X ) in gastric carcinoma [18,35]. ST3GAL6 is also linked to the synthesis of sLe X and the generation of E-selectin ligands [36,37]. Recently, ST3GAL6 was found to be critical to bone marrow homing and resistance to therapy in multiple myeloma [36], and a follow-up study demonstrated this can be inhibited with the E-selectin antagonist GMI-1271 [37].…”

“…ST3GAL6 is also linked to the synthesis of sLe X and the generation of E-selectin ligands [36,37]. Recently, ST3GAL6 was found to be critical to bone marrow homing and resistance to therapy in multiple myeloma [36], and a follow-up study demonstrated this can be inhibited with the E-selectin antagonist GMI-1271 [37]. Other cancer-associated sialyltrasferases include ST6GalNAc1 (which catalyses the cancer-associated sTn antigen) and is associated with metastasis [8,27,[38][39][40][41][42][43], and ST6GALNAC2, which has been identified as a metastasis suppressor in breast cancer patients and could be used to stratify patients for treatment with galectin-3 inhibitors [44,45].…”

“…Plays a key role in selectin ligand synthesis through generation of sLe X . [36,37] ST6GALNAC1 Catalyses the sTn antigen and is associated with metastasis. [8,27,[38][39][40][41][42][43] ST6GALNAC2 Metastasis suppressor in breast cancer.…”