Abstract
Simple SummaryAntibody-drug conjugates (ADCs) constitute new and effective therapies in cancer. However, resistance is frequently observed in treated patients after a given period of time. That resistance may be present from the beginning of the treatment (primary or de novo resistance) or raise after an initial response to the ADC (secondary resistance). Knowing the causes of those resistances is a necessity in the field as it may help in designing strategies to overcome them. Because of that, it is necessary to develop models that allow the identification of mechanisms of resistance. In this review, we present different approaches that have been used to model ADC resistance in the preclinical setting, and that include the use of established cell lines, patient-derived ex vivo cultures and xenografts primarily or secondarily resistant to the ADC. In the last 20 years, antibody-drug conjugates (ADCs) have been incorporated into the oncology clinic as treatments for several types of cancer. So far, the Food and Drug Administration (FDA) has approved 11 ADCs and other ADCs are in the late stages of clinical development. Despite the efficacy of this type of drug, the tumors of some patients may result in resistance to ADCs. Due to this, it is essential not only to comprehend resistance mechanisms but also to develop strategies to overcome resistance to ADCs. To reach these goals, the generation and use of preclinical models to study those mechanisms of resistance are critical. Some cells or patient tumors may result in primary resistance to the action of an ADC, even if they express the antigen against which the ADC is directed. Isolated primary tumoral cells, cell lines, or patient explants (patient-derived xenografts) with these characteristics can be used to study primary resistance. The most common method to generate models of secondary resistance is to treat cancer cell lines or tumors with an ADC. Two strategies, either continuous treatment with the ADC or intermittent treatment, have successfully been used to develop those resistance models.
Highlights
antibody-drug conjugates (ADCs) Structure and Mechanism of ActionADCs are compounds that combine the specificity of a monoclonal antibody with the toxicity of a cytotoxic payload (Figure 1).The goal of these molecules is to transport the cytotoxic agent to tumor cells, maximizing efficacy and minimizing toxicity against non-tumoral tissues [1,2]
It has been reported that alterations in the expression of ABCB1/MDR1/P-gp, ABCC1/MRP1, ABCC2, and ABCG2/BCRP/MXR/ABCP lead to resistance to trastuzumab-DM1 (T-DM1) in preclinical models [23,24,25,26,27]
Nadal-Serrano et al developed models of acquired resistance using the PDX118 cell line obtained from a mouse that was implanted with a cutaneous metastasis of a patient with HER2+ breast cancer
Summary
ADCs are compounds that combine the specificity of a monoclonal antibody (mAb) with the toxicity of a cytotoxic payload (Figure 1). But not mandatory, the antigen must be overexpressed in the cancer cells, a circumstance that facilitates the targeting of the ADC to the tumor with preference to normal tissues expressing the membrane target protein. Another requirement is that the targeted molecule, mainly a protein, must be internalized together with the compound to deliver the cytotoxic agent inside tumor cells [4]. Noncleavable linkers require proteolytic degradation of the ADC to release the active cytotoxic [6] Such a cleavage step is expected to occur in lysosomes, where ADC-target protein complexes are directed upon interaction from the cell surface. This latter ADC includes PE38, a 38 kDa fragment of Pseudomonas exotoxin A that acts as a potent inhibitor of protein synthesis [12]
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