Mapatumumab and
lexatumumab (targeting
death receptor 4 (DR4) and 5 (DR5), respectively) are agonistic TRAIL receptor
antibodies that induce apoptosis in a wide range of
cancer cells. The potency of
mapatumumab and
lexatumumab was assessed in mono
therapy protocols, and the ability to sensitize for
dacarbazine (
DTIC) treatment was explored in ten different
melanoma cell lines. Our data indicated that
melanoma cell lines tend to be resistant to
mapatumumab, most likely due to low expression of DR4, while a dose dependent response to
lexatumumab was observed. Combining
DTIC and
lexatumumab induced an additive or synergistic effect on cell death in the various
melanoma cell lines. The synergistic effect observed in the FEMX-1 cell line was related to enhanced cleavage of Bid in parallel with elevated expression of the
pro-apoptotic proteins Bim, Bax and Bak. Furthermore, the
anti-apoptotic proteins Bcl-XL, cIAP-1, XIAP and livin were down regulated. Cleavage of Bid and down regulation of cIAP-2 and livin were observed in vivo. Altogether, these data suggest a change in the balance between pro- and
anti-apoptotic proteins favoring induction of apoptosis. In the more
therapy resistant cell line, HHMS, no changes in the pro- and
anti-apoptotic proteins were observed. FEMX-1 xenografts treated with
DTIC and
lexatumumab showed reduced growth and increased level of apoptosis compared to the control groups, providing arguments for further evaluation of this combination in
melanoma patients.