Mapatumumab and lexatumumab induce apoptosis in TRAIL-R1 and TRAIL-R2 antibody-resistant NSCLC cell lines when treated in combination with bortezomib

Abstract

Mapatumumab and lexatumumab are fully human monoclonal antibodies that bind and activate human tumor necrosis factor-related apoptosis-inducing ligand receptors 1 and 2, respectively. These antibodies induce apoptosis in various tumor cell types, although the degree of sensitivity can vary from highly sensitive to completely resistant. Importantly, tumor cells that are partially or completely resistant to mapatumumab or lexatumumab can often be sensitized when treated in combination with chemotherapeutic drugs. In this regard, the proteasome inhibitor bortezomib has recently shown synergistic activity against established lymphoma cell lines and primary lymphomas when combined with mapatumumab and lexatumumab. Here, we report similar findings using a panel of human non-small cell lung cancer (NSCLC) cell lines. Specifically, we show that bortezomib rapidly induces sensitivity to mapatumumab and lexatumumab in NSCLC cell lines that are completely resistant to antibody alone and that bortezomib concentrations as low as 25 nmol/L sensitize NSCLC cells to the antibodies. Furthermore, bortezomib at the tested concentration has minimal effect on its own, indicating the combination generates synergistic cytotoxicity. Combination treatment induces activation of the caspase cascade and the effect of the combination is caspase dependent. Bortezomib treatment increases the intracellular levels of several important apoptosis regulators that may mediate enhanced sensitivity to mapatumumab and lexatumumab. These results suggest future evaluation of mapatumumab or lexatumumab in combination with bortezomib is warranted in NSCLC patients.

Targeting inhibitor of apoptosis proteins in combination with dacarbazine or TRAIL in melanoma cells

“…37,38 Similarly, monoclonal agonistic TRAIL receptor antibodies, being superior in stability and ease of administration, are promising alternatives to the TRAIL protein or gene therapy vectors. [39][40][41] Thus, alternative approaches, initiating the same response, but omitting the delivery problems, can be used to evaluate the therapeutic potential of the combination. An additional advantage using IAP inhibitors compared to siRNAs may be their ability to inhibit several IAPs.…”

Monoclonal Antibodies: An Emerging Class of Therapeutics in Non Small Cell Lung Cancer

“…TRAIL-R2 was detected in 82% of NSCLC tumor biopsies [176]. Several antibodies which are TRAIL agonist have been developed [177].…”

Combined modality therapy with TRAIL or agonistic death receptor antibodies

“…Newer agents currently at various stages of clinical development also show promise for combination treatment with TRAIL and death receptor antibodies, including proteasome inhibitors (bortezomib), 125,153,[188][189][190][191] histone deacetylase inhibitors…”