Seminar

Thalidomide scandal and the treatment of cancer.

Vanesa Fernández-Sáiz, PhD

Thalidomide was a drug used to treat morning sickness in pregnant women in the early 1960s that caused serious congenital birth defects. Nowadays, thalidomide derivates are a second-generation of molecules named immunomodulatory drugs (IMiDs) currently in use for the treatment of hematologic malignancies such as multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN) is the primary target for IMiDs. We have previously described a chaperone-like function of CRBN, which stabilizes the transmembrane proteins CD147 and MCT1. Interference with this process is a major means by which IMiDs mediate their anti-tumor and teratotoxic activities. So far, it remained unclear as to how CRBN confers chaperone activity towards its transmembrane client proteins. Here, we suggest CRBN to act as a novel regulator of the HSP90-AHA1 complex, which facilitates proper maturation of transmembrane proteins such as the cystic fibrosis transmembrane conductance regulator (CFTR). Strikingly, the HSP90-CRBN interaction was abrogated upon IMiD-treatment, thus explaining CRBN-dependent IMiD-induced destabilization of its transmembrane clients. Interestingly CFTR was also destabilized upon IMID treatment. Our results suggest CRBN to exert a co-chaperone function within the HSP90-AHA1 complex to mediate transmembrane protein maturation.