Clinical and in vitro resistance to bexarotene in adult T-cell leukemia: loss of RXR- receptor

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 responded rapidly to combination therapy of bexarotene and interferon (IFN)2b with complete clinical response. 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 retinoid X receptor (RXR) subunits, RXRand RXR, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXRand RXRby resistant cells. We assessed RXRand RXRexpression by Western blot analysis and found that resistant cells had significantly decreased RXRexpression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXRreceptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies. (Blood. 2008;112: 2484-2488)