Dacarbazine and the Agonistic TRAIL Receptor-2 Antibody Lexatumumab Induce Synergistic Anticancer Effects in Melanoma

Abstract

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.

Synthetic retinoid CD437 induces apoptosis and acts synergistically with TRAIL receptor-2 agonist in malignant melanoma

“…In line with what has been observed by others [149], treatment with the TRAIL agonist decreased the viability in both cell lines as a single agent. When combining Lexatumumab with CD437, the cell viability was further reduced and resulted in a synergistic effect.…”

“…Combinational therapy represents a potential strategy for treating TRAIL resistant cancers. In line with this, Lexatumumab has shown promising results in preclinical studies of melanoma, in particular in combination with other agents such as Dacarbazine[149] and Anisomycin[150]. Treatment with Lexatumumab is generally well tolerated as assessed in a Clinical phase I trial of pediatric patients with solid tumours[151].…”

Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10

“…Six of the nine validated agents met the prioritization criteria of imparting >20% increased reduction in cell viability over the expected observations and a >25% reduction in absolute cell viability with the combination: azacitidine, bortezomib, dacarbazine, hydroxyurea, sorafenib, and vismodegib (Figure 2C). Synergy between TRAIL and bortezomib, dacarbazine, hydroxyurea, or sorafenib has been previously reported (3, 5, 6). Examining monoagent and combinatorial activity, we found that adding vismodegib to ONC201 did not result in improved activity compared to monoagent ONC201, but rather reversed surprising agonistic growth effects of monoagent vismodegib that we observed in several cell lines.…”

Phage display-derived human antibodies in clinical development and therapy

“… 126 Like mapatumumab, lexatumumab mediated synergistic effects in combination with chemotherapeutics. 135 In combination with radiation, lexatumumab showed some clinical activity in pediatric solid tumors. 136 …”