Owing to deregulated growth, cancer cells experience more stress than normal counterparts, and thus are highly dependent on adaptive stress responses. Such non-oncogene addiction offers targets with previously unpredicted therapeutic specificity (1). Paradigmatic is multiple myeloma (MM, ~2% of all cancer deaths), where proteasome inhibitors, prototypical negative proteostasis regulators, emerged as potent therapeutic agents, whose clinical use now extends to other cancers. However, despite substantial therapeutic advancements, MM remains incurable, due to primary and secondary drug resistance, calling for novel targeted therapies (2,3).
We recently discovered an essential role played by autophagy in long-lived bone marrow plasma cells, normal myeloma counterparts (4). We then challenged this role in MM, which proved exquisitely dependent on autophagy for organelle homeostasis and cell survival. In particular, we disclosed that MM cells depend on the prototypic autophagy adapter protein p62/SQSTM1 for survival, proteostasis, and proteasome inhibitor resistance (5). Dissecting the exact functions of p62 in MM cells holds promise for the informed design of novel potent targeted therapies (6).
- Luo J, Solimini NL, Elledge SJ. Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 2009; 136:823-37 2. Rajkumar SV. Treatment of multiple myeloma. Nat Rev Clin Oncol 2011; 8:479-491 3. Auner HW, Cenci S. Recent advances and future directions in targeting the secretory apparatus in multiple myeloma. Br J Haematol 2015; 168:14-25 4. Pengo N, Scolari M, Oliva L, et al. Plasma cells require autophagy for sustainable immunoglobulin production. Nat Immunol 2013; 14:298-305 5. Milan E, Perini T, Resnati M, et al. A plastic SQSTM1/p62-dependent autophagic reserve maintains proteostasis and determines proteasome inhibitor susceptibility in multiple myeloma cells. Autophagy 2015; 11(7):1161-78 6. Milan E, Fabbri M, Cenci S. Autophagy in Plasma Cell Ontogeny and Malignancy. J Clin Immunol. 2016 May;36 Suppl 1:18-24