title: Why imatinib remains an exception of cancer research.
abstract: The archetype driving the drug targeting approach to cancer therapy is the success of imatinib against chronic phase chronic myeloid leukemia (CML-CP). Molecular targeting success of this magnitude has yet to be repeated for most solid tumors. To answer why imatinib remains an exception of cancer research, we summarize key features and patterns of evolution that contrast CML-CP from prostate cancer, an example of a solid tumor that also shares a signature fusion gene. Distinctive properties of CML-CP include: a large cell population size that is not geographically constrained, a highly penetrant dominant oncogene that sweeps the entire cell population, subsequent progressive and ordered clonal genetic changes, and the effectiveness of molecular targeting within the chronic phase, which is comparable to the benign phase of solid tumors. CML-CP progression resembles a clonal, stepwise model of evolution, whereas the pattern of solid tumor evolution is highly dynamic and stochastic. The distinguishing features and evolutionary pattern of CML-CP support why the success of imatinib does not carry over to most solid tumors. Changing the focus of cancer research from a gene-based view to a genome-based theory will provide insight into solid tumor evolutionary dynamics.
authors.affiliation: Center for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, Michigan, USA.
authors.forename: Steven D
authors.initials: SD
authors.lastname: Horne
authors.forename: Joshua B
authors.initials: JB
authors.lastname: Stevens
authors.forename: Batoul Y
authors.initials: BY
authors.lastname: Abdallah
authors.forename: Guo
authors.initials: G
authors.lastname: Liu
authors.forename: Steven W
authors.initials: SW
authors.lastname: Bremer
authors.forename: Christine J
authors.initials: CJ
authors.lastname: Ye
authors.forename: Henry H Q
authors.initials: HH
authors.lastname: Heng
mesh_terms: D000818:Animals; D001549:Benzamides / Q000627:therapeutic use*; D018450:Disease Progression; D006801:Humans; D000068877:Imatinib Mesylate; D015466:Leukemia, Myeloid, Chronic-Phase / Q000188:drug therapy*; D010879:Piperazines / Q000627:therapeutic use*; D011743:Pyrimidines / Q000627:therapeutic use*
chemical_list: D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate