Multiple myeloma (MM) is a clonal B-cell hemopathy, characterized by the accumulation of malignant plasma cells in the bone marrow[1, 2]. This neoplasia accounts for approximately 2% of all cancers and 20% of hematologic ones, being the second most frequently diagnosed hematological malignancy[3]. Even though nowadays it is still considered a non-curable disease, its prognosis has significantly improved thanks to the development of new therapies, such as proteasomal inhibitors or immunomodulatory drugs[4–6]. Moreover, the field of immunotherapy has irrupted with strength in this field with the incorporation to the clinic of antibodies targeting CD38, bispecific antibodies targeting B-cell maturation antigen (BCMA) or G-protein coupled receptor family C group 5 member (GPRC5D) and CD3[7, 8], or antibody-drug conjugates directed to BCMA, such as belantamab mafodotin[9]. Moreover, interest has been paid to the development of antimyeloma therapies based on CAR-T cells directed to BCMA[10]. Currently, selection of the treatment for a patient with MM is considered multifactorial[11], taking into account the patient's physical condition, efficacy of strategies and drug resistance.
Apoptosis is a critical event for tissue homeostasis and cellular development, and its deregulation often occurs during tumor progression and/or chemoresistance by mechanisms not yet fully elucidated[12]. The apoptotic machinery is mainly driven by two different routes, namely the intrinsic and extrinsic pathways. The intrinsic pathway initiates at the mitochondria[12, 13], while the extrinsic pathway is triggered at the cell membrane upon binding of death-inducing polypeptides to their receptors expressed at the cell surface. Both signaling pathways converge on a common machinery which includes members of a family of cysteine proteases called caspases[14]. There are two types of these proteins: initiator and executor caspases. Initiator caspases such as caspases 2, 8, 9 and 10 are activated in response to stress signals or cell damage, while executor caspases such as caspases 3, 6 or 7, are responsible for direct proteolysis of different substrates leading to cell death[15].
Inducing apoptotic cell death has been proposed as an antitumoral strategy[16, 17]. In fact, the BCL2 inhibitor venetoclax has received approval for the treatment of acute myeloid leukemia[18]. Death receptor activation by specific ligands has received attention due to the fact that receptors for these ligands may be more expressed in tumoral tissues with respect to normal tissue counterparts[19]. Such is the case for the TNF-Related Apoptosis-Inducing Ligand (TRAIL)[15, 20]. This ligand is assembled as a soluble homotrimer that interacts with its receptors. Five TRAIL receptors have been described: TRAIL-R1 or DR4 (TNFRSF10A, Tumor Necrosis Factor Receptor SuperFamily member 10A), TRAIL-R2 or DR5 (TNFRSF10B, Tumor Necrosis Factor Receptor SuperFamily member 10B), TRAIL-R3 or DcR1, TRAIL-R4 or DcR2 and a soluble receptor called osteoprotegerin (OPG)[21]. Importantly, DcR1, DcR2 and OPG lack a cytoplasmic death domain and are therefore unable to transduce signaling. Moreover, since they may interact with soluble TRAIL but do not transduce a signal, they are expected to antagonize the proapoptotic action of TRAIL. Therefore, only DR4 and DR5 present this complete structure and can efficiently bind TRAIL and transduce the death signal to target cells. Upon binding to the ligand, DR4 or DR5 may form homo- or heterotrimeric receptor structures that are then able to recruit proteins that interact with the intracellular region of the receptor, including Fas-Associated Death Domain (FADD) protein and pro-caspase 8. This membrane-associated complex, known as DISC (Death Initiating Signaling Complex) will trigger the death pathway[22–24]. In addition to this complex, cytoplasmic inhibitors such as c-FLIP (FADD-like IL-1β-converting enzyme)-inhibitory protein, can restrict caspase activation and cause resistance to TRAIL-mediated apoptosis[25].
Preclinical studies in MM have shown that TRAIL can trigger cell death of malignant plasma cells while sparing hematopoietic stem cells[26, 27]. Moreover, it has been reported that TRAIL may be used to overcome resistance to conventional antimyeloma treatments[28, 29]. Mechanistically, activation of TRAIL receptors in myeloma using agonistic antibodies promoted cleavage of the antiapoptotic protein MCL-1L[30]. Interestingly, the antimyeloma action of TRAIL did not appear to correlate with the pro-caspase 8/c-FLIP ratio[31]. These precedents stimulated the testing of TRAIL for the therapy of MM.
Several clinical trials, using circularly permuted TRAIL have shown antimyeloma activity in refractory MM, either used alone or in combination with thalidomide and dexamethasone[32, 33]. The results of the latter phase II trial showed that the combination of TRAIL with thalidomide and dexamethasone resulted in an overall response rate of 38.3%, while in the case of thalidomide and dexamethasone it was of 25%. Moreover, the TRAIL combination doubled the progression free survival time with respect to the two standard of care drugs combined. These data have been updated in a recent phase III trial that has demonstrated the beneficial effects of combining the TRAIL derivative aponermin with dexamethasone and thalidomide in MM refractory patients [34]. These clinical results are promising, but also showed that not all patients respond to TRAIL, and those which respond ultimately relapse. That fact opens the question of how to better optimize the therapy of MM patients with TRAIL and how to identify patients refractory versus those that may respond.
To better understand the molecular basis of TRAIL action and resistance in the context of MM, we generated TRAIL-resistant models by continuously exposing MM cells to this agent. These studies allowed the identification of mechanisms of resistance to the death-inducing action of TRAIL. Moreover, genomic analyses of the resistant cells allowed identification of pathways deregulated in those cells, that could be used to develop strategies to overcome TRAIL-induced resistance.