The immune-modulating therapeutic agent lenalidomide is a broadly active therapeutic agent for a variety of hematologic malignancies including multiple myeloma, del(5q-) myelodysplastic syndrome, acute myeloid leukemia, non-Hodgkin lymphoma, Hodgkin disease, and chronic lymphocytic leukemia. This has prompted considerable interest in developing third-generation immune modulation agents, such as pomalidomide. Several of these are currently in clinical trials for multiple myeloma where promising responses have been observed. One of the perplexing things about this class of medications is the diverse potential mechanism(s) of action, including immune effector cell activity enhancement, tumor microenvironment interference, and direct tumor-directed apoptosis. To date, very few studies have identified pathways upon which this class of agents acts or if the different agents have divergent mechanisms of action. In this paper, Drs. Xu and Xie and their colleagues from Celgene, demonstrated that pomalidomide activates monocytes by activating specific small-molecular-weight G-proteins, RhoA and Rac1, with subsequent enhancement of F-actin formation, stabilization of microtubules, and increase in cell migration. When examined in T cells, similar findings were observed with both pomalidomide and lenalidomide. RhoA activation with lenalidomide was tied to T-cell production of the “general officer” cytokine IL-2 that, in many prior publications, was shown to be required for lenalidomide-induced activation of other immune effector cells. This activation was not direct, thereby providing a lead for other investigators to pursue just how this is occurring in future investigations of this novel class of drugs.
While the mechanisms of action of many therapeutic agents for cancer remain unknown, understanding how an agent works is an important step in including a therapy in rational combinations, and also in fully appreciating its potential. Lenalidomide is one such agent that we know for certain is effective for the treatment of a host of hematologic malignancies, and yet our understanding of its mechanism(s) of action is quite limited. This study, therefore, is important to the field in that it directs other researchers to pursue further the ability of members of this class of drug to enhance cell membrane-based signaling and activation of RhoA along with related family members.
Dr. Byrd indicated no relevant conflicts of interest.