An article published in the December 2016 issue of Molecular Cancer Therapeutics by Frank Loganzo, Matthew Sung and Hans-Peter Gerber, working for Oncology R&D, Pfizer, Pearl River, New York, describes how drug resistance limits the effectiveness of cancer therapies. The authors review recent progress in the understanding of Antibody-drug conjugates or ADC resistance, including approaches to create pre-clinical ADC-refractory models and to characterize their emerging mechanisms of resistance.

Diverse therapies
Despite attempts to develop curative anticancer treatments, tumors evolve evasive mechanisms limiting durable responses. Hence, diverse therapies are used to attack cancer, including cytotoxic and targeted agents.

Antibody-drug conjugates or ADC are biotherapeutics designed to deliver potent cytotoxins to cancer cells via tumor-specific antigens. Little is known about the clinical manifestations of drug resistance to this class of therapy. Recent preclinical studies have, however, revealed potential mechanisms of resistance.

Multifactorial modes of resistance
Because ADCs are a combination of antibody and small molecule cytotoxin, multifactorial modes of resistance are emerging that are inherent to the structure and function of the ADC. Decreased cell-surface antigen reduces antibody binding, whereas elevated drug transporters such as MDR1 and MRP1 reduce effectiveness of the payload.

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Inherent to the uniqueness of the ADC, other novel resistance mechanisms are emerging, including altered antibody trafficking, ADC processing, and intracellular drug release. Most importantly, the modular nature of the ADC allows components to be switched and replaced, enabling development of second-generation ADCs that overcome acquired resistance.

Last editorial review: December 18, 2016

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