Tailoring Sec61 inhibitors for precision medicine

Daniela Ricci (Institut Pasteur, Paris)

18 janvier 2024


Infos pratiques

12:00 - 13:00
Salle Rosalind Franklin
Accès mobilité réduite

Mycolactone is a lipid toxin produced by Mycobacterium ulcerans, the causative agent of the neglected tropical disease Buruli ulcer, characterized by extensive skin ulceration surprisingly devoid of pain and inflammation. Decades of research unveiled that mycolactone is a potent inhibitor of the protein translocon Sec61, the gate of the secretory pathway in eukaryotic cells. This discovery not only shed light on the central role Sec61 plays in inflammation but also illuminated its particular significance for cancer cell biology.

Using mycolactone, our laboratory demonstrated the heightened sensitivity of multiple myeloma (MM) cancerous plasma cells to Sec61 inhibition, resulting in apoptosis of patient-derived MM cells in vitro and delayed MM growth in animal models. Such sensitivity resulted from an unconventional endoplasmic reticulum stress response marked by the absence of regulatory chaperones. Notably, mycolactone exhibited a synergistic effect with the current first-line treatments (proteasome inhibitors and lenalidomide), offering hope for relapsed/refractory MM cases. These findings opened up medical perspectives into the potentiality of Sec61 inhibition for MM therapy and beyond. We are now working to develop safe, tailored Sec61 blockers for a wide range of indications, marking a pioneering approach in drug development.

Invited by the committee for Post-doc seminar series.

Selected publications

  • Bracchi-Ricard V, Nguyen K, Ricci D, Gaudette B, Henao-Meija J, Brambilla R, Martynyuk T, Gidalevitz T, Allman D, Bethea JR and Argon Y. Increased activity of IRE1 improves the clinical presentation of EAE. FASEB J. 2023 Dec;37(12):e23283.
  • Domenger A., Ricci D., Mayau V., Majlessi L., Marcireau C., Dadaglio G., Demangel C. (2023). Sec61 blockade therapy overrides resistance to proteasome inhibitors and immunomodulatory drugs in multiple myeloma., Frontiers in Oncology 13(): 1110916.
  • Ricci, D., & Demangel, C. (2023). From Bacterial Toxin to Therapeutic Agent: The Unexpected Fate of Mycolactone. Toxins, 15(6), 369.
  • Di Risola, D., Ricci, D., Marrocco, I., Giamogante, F., Grieco, M., Francioso, A., ... & Altieri, F. (2022). ERp57 chaperon protein protects neuronal cells from Aβinduced toxicity. Journal of Neurochemistry, 162(4), 322-336.
  • Ricci D, Gidalevitz T and Argon Y. The Special Unfolded Protein Response in Plasma Cells. Immunological Reviews, 2021 Sep;303(1):35-51.
  • Ricci D, Tutton S, Marrocco I, Mingjie Y, Blumenthal D, Eletto D, Vargas J, Boyle S, Fazelinia H, Qian L, Suresh K, Taylor D, Paton J, Paton A, Tang CH, Hu CC, Radhakrishnan R, Gidalevitz T and Argon Y. An Interdomain Helix in IRE1α Mediates the Conformational Change Required for the Sensor’s Activation. J Biol. Chem., Jan-Jun 2021;296:100781.
  • Ricci D, Saunders J, Tutton S, Gidalevitz T, Argon Y. The Sensor IRE1 Couples Stress Detection to Protein Synthesis. The FASEB Journal 35(S1), May 2021.
  • Ricci D, Marrocco I, Blumenthal D, Dibos M, Eletto D, Vargas J, Boyle S, Iwamoto Y, Chomistek S, Paton JC, Paton AW, and Argon Y- Clustering of IRE1a Depends on Sensing ER Stress but not on its RNase Activity. The FASEB Journal, 2019 Sep;33(9):9811-9827.