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)-alpha2b 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-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-beta expression by Western blot analysis and found that resistant cells had significantly decreased RXR-alpha expression compared with pretherapy 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.
Lin
Julie H
JH
Department of Dermatology, University of Pennsylvania, Philadelphia 19104, USA. julie.lin@mail.mcgill.ca
Kim
Ellen J
EJ
Bansal
Anand
A
Seykora
John
J
Richardson
Stephen K
SK
Cha
Xian-Yuan
XY
Zafar
Sarosh
S
Nasta
Sunita
S
Wysocka
Maria
M
Benoit
Bernice
B
Rook
Alain H
AH
Fakharzadeh
Steven S
SS
D000077610:Bexarotene; D019008:Drug Resistance, Neoplasm; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000188:drug therapy*; D008198:Lymph Nodes / Q000473:pathology; D008297:Male; D008875:Middle Aged; D012008:Recurrence; D047490:Retinoid X Receptor alpha / Q000032:analysis / Q000172:deficiency*; D012878:Skin Neoplasms; D013601:T-Lymphocytes / Q000187:drug effects; D013764:Tetrahydronaphthalenes / Q000494:pharmacology* / Q000627:therapeutic use
D047490:Retinoid X Receptor alpha; D013764:Tetrahydronaphthalenes; D000077610:Bexarotene