Downregulation of mTORC1 Signaling is Associated with Increased Sensitivity to Protein Synthesis Perturbations in Multiple Myeloma.

Protein synthesis is critical for the survival and proliferation of multiple myeloma cells. mTORC1 signaling, through its downstream effectors S6K1 and S6, regulates ribosome biogenesis and protein homeostasis. However, the relative sensitivity of multiple myeloma cells to perturbations in protein synthesis compared with other cancer types remains unclear. In addition, the role of S6K1 and S6 signaling in the response to translational stress and the therapeutic potential of mTORC1 inhibition in multiple myeloma are not fully understood. Multiple myeloma and non-myeloma cancer cell lines were subjected to protein synthesis perturbations. Changes in mTORC1 signaling, including S6K1 and S6 activity, were analyzed. Cellular responses, including proliferation and apoptosis, were assessed. The mechanisms of protein synthesis were also evaluated under these conditions. The effects of the mTORC1 inhibitor Torin1 were examined across cell lines. Sensitivity to protein synthesis stress and mTORC1 inhibition was compared between multiple myeloma and other cancer types, including bortezomib-resistant cells. Multiple myeloma cell lines exhibited heightened sensitivity to protein synthesis perturbations, accompanied by marked suppression of S6K1 and S6 signaling and reduced global protein synthesis. This increased sensitivity resulted in decreased proliferation and increased apoptosis compared to non-myeloma cancer cell lines. Treatment with the mTORC1 inhibitor Torin1 produced a pronounced inhibitory effect in multiple myeloma cells. Notably, cell lines resistant to protein synthesis perturbations showed increased sensitivity upon mTORC1 inhibition. Furthermore, the bortezomib-resistant RPMI-8226 cell line was resensitized to bortezomib following Torin1 treatment. These findings establish a mechanistic link between mTORC1 signaling, protein synthesis stress, and multiple myeloma. Targeting mTORC1 signaling enhances sensitivity to translational stress and overcomes drug resistance, highlighting a potential therapeutic vulnerability in multiple myeloma.