Hypoxia appears to induce chemoresistance to proteasome inhibitors (PIs) among patients being treated for multiple myeloma (MM), according to research published in Oncogene. Targeting SENP1 or the steroid receptor coactivator-3 (SRC-3) may help to overcome this resistance.
Although there is significant clinical heterogeneity in MM and a wide array of available treatments, PIs have been shown to be an effective strategy, but chemoresistance remains a problem among patients who receive these therapies.
Dynamic post-translational modifications, such as SUMOylation, have been previously shown to be important for disease trajectory. Hypoxia is known to be involved in the development of chemoresistance, but the molecular underpinnings are not yet well established.
Previous study has also suggested that SENP-1-mediated modification of SRC-3 may play a role in hypoxia, and consequently chemoresistance. For this mouse model and patient xenograft-based study, researchers investigated this link, as well as the possibility that SENP1 and SRC-3 inhibitors may be an effective strategy among patients with MM who develop chemoresistance to PIs.
The mouse model analysis showed that SENP-1 is a crucial modifier of the SRC-3 protein via deSUMOylation. Any depletion of SENP-1 appeared to attenuate SRC-3 stability; knockdown of SENP-1 accelerated this process — and suggested the possibility of overcoming chemoresistance to PIs.
In both the mouse model and patient-derived xenograft, Momordin Ιc, an SENP-1 inhibitor, increased cell sensitivity to PIs.
“In summary, this study provides new knowledge for understanding the chemoresistance of MM cells to PIs under hypoxia condition, and further emphasizes the importance of SRC-3 in regulating sensitivity to PIs via its interaction with the SUMO-specific protease SENP1,” the authors wrote in their report.
Guo J, Lv Y, Wang S, et al. Hypoxia induces chemoresistance to proteasome inhibitors through orchestrating deSUMOylation and ubiquitination of SRC-3 in multiple myeloma. Oncogene. Published online October 8, 2022. doi:10.1038/s41388-022-02494-5