Understanding and circumventing resistance to anticancer monoclonal antibodies

Abstract

With the widespread use of therapeutic monoclonal antibodies in the treatment of patients with cancer, resistance to these agents has become a major issue. Preclinical models of drug action or resistance have contributed to unravel the main mechanisms of resistance, involving both tumor-associated and host related factors. However our understanding of how a monoclonal antibody destroys cancer cells in a patient and why it one day stops being effective are still far from being complete. This review focuses on the available data on mechanisms of action and resistance to rituximab and includes some additional information for other monoclonal antibodies. Innovative approaches designed to overcome resistance, such as combination immunotherapy, costimulation with cytokines or growth factors are presented.

Figure 1

Summary of mechanisms that influence rituximab efficiency. These include host-related factors (including pharmacokinetics and polymorphisms of key molecules such as FcgammaIII) and tumor cell-related factors.

Figure 2

A schematic diagram that illustrates potential cellular mechanisms of resistance to rituximab following its interaction with CD20. Acquired resistance can be associated with significant change in CD20 antigen expression, deficient redistribution into lipids raft domains or alteration in raft components and decreased calcium mobilization. Alterations in intracellular pathways, such as those involving p38 MAPK, NFκB, ERK1/2, Akt, could be implicated in resistance. An enhanced activation of NFκB and ERK1/2 can lead to overexpression of Bcl2, Bcl-x_L and Mcl-1 thereby inhibiting apoptosis by dysregulating mitochondrial cell-intrinsic and extrinsic pathways. Moreover, the transcription repressor YY1 can negatively regulate Fas and Trail receptor expression and confer resistance to apoptosis.