Dodging the bullet: therapeutic resistance mechanisms in pediatric cancers

Abstract

While advances in the treatment of pediatric cancers have improved survival to > 80% across all tumor types, drug resistance continues to limit survival for a considerable number of patients. We review the known mechanisms of resistance in pediatric cancers, including processes that impair conventional chemotherapies, newer classes of targeted small molecule antineoplastic drugs, and monoclonal antibodies. We highlight similarities and differences in treatment approach and resistance between pediatric and adult cancers. We also discuss newer areas of research into drug resistance, including extracellular and immune factors.

Keywords: BCL2; Tumor microenvironment; chemoresistance; drug efflux; inhibition of apoptosis; pediatric cancer.

Figure 1

Mechanisms of therapeutic resistance in pediatric cancers. (1) Altered drug metabolism, either at the liver, in the bloodstream, or in the cell; (2) Altered drug influx/effux; (3) Disruption of response to DNA damage; (4) Inhibition of mitochondrial/cytochrome c/ROS-mediated cell death; (5) Epigenetic dysregulation; (6) miRNA dysregulation; (7) Mutations/amplification of tyrosine kinases; (8) Abnormal expression/downregulation of cell surface markers and targets of monoclonal antibodies and other immune therapies; (9) Activation of telomerase/ALT. (10) Tumor microenvironment enabling viability