Clinical and in vitro resistance to bexarotene in adult T cell leukemia: loss of RXR-alpha receptor. Blood [Blood] Journal article

The oral rexinoid, bexarotene (Targretin), is widely used for treatment of cutaneous T-cell lymphomas (CTCL). We recently reported the first case of adult T-cell Leukemia/Lymphoma (ATLL) that rapidly responded to combination therapy of bexarotene and interferon (IFN)-alpha2b with complete clinical response.(1) We demonstrated that bexarotene induced apoptosis of the patient's malignant peripheral blood T-cells in vitro. However, our patient developed skin and nodal relapse 180 days after starting treatment. We now demonstrate that his peripheral blood malignant T-cells became resistant to bexarotene-induced apoptosis. We investigated potential mechanisms that may cause aberrations in the RXR receptor subunits, RXR-alpha and RXR-beta, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR-alpha and RXR-beta by resistant cells. We assessed RXR-alpha and RXR-betaexpression by Western blot analysis and found that resistant cells had significantly decreased RXR-alpha expression compared to pre-therapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR-alpha receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.

Blood [Blood]