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.

HEK293 in cell biology and cancer research: phenotype, karyotype, tumorigenicity, and stress-induced genome-phenotype evolution

“…Importantly, the transfection of an empty vector DNA itself may also destabilize karyotype and impact phenotype. The theoretical basis for explanation of stress-induced genome-phenotype evolution provides the genome theory of cancer (reviewed in Heng, 2009;Heng et al, 2009Heng et al, , 2010Heng et al, , 2011Heng et al, , 2013Horne et al, 2013;Stevens et al, 2013;Duesberg et al, 2005Duesberg et al, , 2007Duesberg et al, , 2011.…”

Heterogeneity of Cell Death

“…Fusion proteins have altered function such as the BCR-ABL translocation in chronic myelogenous leukemia which results in a constitutively active ABL kinase that drives proliferation. Other fusion events have been associated with increased proliferation in prostate cancer [Horne et al, 2013a]. Genome level change does not, however, only affect cell death heterogeneity by creating abnormal fusion proteins.…”

Evolutionary mechanism unifies the hallmarks of cancer

“…While specific molecular targeting may be an ideal strategy in a stable system, it is not a reasonable approach for an unstable, evolving system that is characterized by an unlimited number of potential pathways and dynamic changes to the transcriptome as a result of genome system alteration. 9,64,65,73 Therefore, to achieve a clinically relevant understanding, we must utilize approaches that account for inter and intra-tumoral heterogeneity in cancer. 74 Such unpredictability can be most obvious when dealing with treatment.…”

“…As previously demonstrated, high doses of chemotherapeutics intended for high rates of tumor cell death that are commonly prescribed to patients can trigger chaotic genome formation and rapid changes of genome systems, which may lead to rapid emergence of an aggressive, drug-resistant tumor subpopulation. [24][25][26]57,73 Thus, the genome theory calls into question the current standard protocols of chemotherapy, as drug intervention could paradoxically promote cancer evolution when applied in the wrong phase. 75,76 Therapeutic strategies should include the aim to reduce system stress to avoid triggering fast cancer evolution.…”