Clinical and in vitro resistance to bexarotene in adult T cell leukemia: loss of RXR-alpha 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)-α2b 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, RXR-α and RXR-β, to account for these findings. Sequence analysis did not reveal acquisition of mutations in the genes encoding RXR-α and RXR-β by resistant cells. We assessed RXR-α and RXR-β expression by Western blot analysis and found that resistant cells had significantly decreased RXR-α expression compared with pretherapy bexarotene-sensitive cells. Our findings indicate that reduced expression of the RXR-α receptor subunit may represent a mechanism for resistance to bexarotene in T-cell malignancies.