Reason for resistance to immune drugs found in blood cancers

November 2021 Science Nalinee Pandey
Molecular model of antibody taking part in immune defense. Molecule of immunoglobulin, 3D illustration

Researchers have identified a key gene, USP15, that prevents cancers cells from responding to drug treatment.

Hematological malignancies mainly affect the function and process of making blood cells. The most commonly occurring blood cancer is multiple myeloma (MM). As the affected cells in MM are responsible for producing antibodies against infection, patients suffering from MM have a very weak immune system, and thus are highly susceptible to any kind of infection.

Immunomodulatory drugs (IMiDs) such as thalidomide, lenalidomide, and pomalidomide have revolutionized the treatment landscape of MM treatment, as a high number of patients positively respond to IMiDs.  However as observed in many single drug therapies, besides a few rare exceptions, resistance to IMiDs is invariable observed in almost all the patients. A study by Dr. Thang Van Nguyen was recently published in the recent issue of PNAS. The researcher has identified a protein called USP15 whose expression is elevated in cancer cells which develop resistance to the standard IMiDs.

The standard IMiDs function by targeting cancer cells which have unique ubiquitin tags, and thus initiate the process of cell degradation. However, in the case of MM cells that have high expression of USP15, this protein removes these ubiquitin tags from the cancer cells. The absence of ubiquitin tags from MM cells prevents degradation by IMiDs and thus results in unresponsiveness to these drugs.

This work shows that USP15 can be used as a biomarker for distinguishing between patients who will respond to IMiDs. Moreover, combining IMiDs with USP15 inhibition would lead to a better response in MM patients.

This study is of fundamental relevance for the treatment of MM patients, because this knowledge could lead us to discover whether a USP15 inhibitor in combination with other drugs will be more effective to treat cancers. Further studies will be required to determine the best combination to improve clinical outcomes of patients with multiple myeloma and other types of cancer.


Nguyen T Van. USP15 antagonizes CRL4(CRBN)-mediated ubiquitylation of glutamine synthetase and neosubstrates. Proc Natl Acad Sci U S A. 2021 Oct;118(40).