Somatic alterations as the basis for resistance to targeted therapies

J Pathol. 2014 Jan;232(2):244-54. doi: 10.1002/path.4278.


Recent advances in genetics and genomics have revealed new genes and pathways that are somatically altered in human malignancies. This wealth of knowledge has translated into molecularly defined targets for therapy over the past two decades, serving as key examples that translation of laboratory findings can have great impact on the ability to treat patients with cancer. However, given the genetic instability and heterogeneity that are characteristic of all human cancers, drug resistance to virtually all therapies has emerged, posing further and future challenges for clinical oncology. Here we review the history of targeted therapies, including examples of genetically defined cancer targets and their approved therapies. We also discuss resistance mechanisms that have been uncovered, with an emphasis on somatic genetic alterations that lead to these phenotypes.

Keywords: cancer; drug resistance; somatic alterations; targeted therapies.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Review

MeSH terms

  • Animals
  • Antineoplastic Agents / therapeutic use*
  • Biomarkers, Tumor / genetics*
  • Drug Discovery
  • Drug Resistance, Neoplasm / genetics*
  • Genetic Predisposition to Disease
  • Humans
  • Molecular Targeted Therapy*
  • Neoplasms / drug therapy*
  • Neoplasms / genetics*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Phenotype
  • Signal Transduction / drug effects
  • Signal Transduction / genetics


  • Antineoplastic Agents
  • Biomarkers, Tumor