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Why Chemotherapy Does Not Work: Cancer Genome Evolution and the Illusion of Oncogene Addiction

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Evolutionary Thinking in Medicine

Abstract

A long-held and dominating view that cancer is a genetic disease caused by deterministic sequential mutations in a restricted number of cancer-driver genes (oncogenes and tumour suppressor genes), occurring in a continuous linear pattern of tumour progression, and directly determining the hallmarks of cancer, has now been disproved. This view is tied to the “oncogene addiction” concept: the idea that tumour cells are dependent on a single activated oncogenic protein or pathway to maintain their malignant properties. However, this has also been challenged by both the observation of tumour relapses after the inactivation of oncogene in mouse models and the failure of targeted therapies in clinical trials. In this chapter, we adopt an evolutionary perspective to consider that the majority of tumours contain a heterogeneous cell population with many random genome alterations and extensively rewired signalling networks. In this context, chromosome instability (CIN) drives genomic and (epi)genetic heterogeneity, rewires and creates new genetic networks due to the dynamic alterations of transcriptome/proteome, and eventually generates the diverse tumour cell phenotype variants, which constitutes the basis for cancer evolutionary selection and multidrug resistance. Any factors or stresses, including chemotherapy, that contribute to CIN may promote the evolution of cancer. In this chapter, we review (i) the genome theory of cancer, (ii) the role of CIN for cancer evolution, and (iii) why cancer mouse models do not recapitulate a natural tumour. The implications of a stochastic model of genome evolution for chemotherapy are discussed.

Vadym Kavsan—Deceased

I dedicate this chapter to the memory of my tutor, professor Vadym Kavsan, a prominent Ukrainian scientist (1939–2014). His patience, advice, guidance, and attention to detail were invaluable. His original ideas and striking personality will inspire me in future.

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Acknowledgments

This work was supported in frames of the programs “Fundamental grounds of molecular and cell biotechnologies” and “Nanotechnologies and nanomaterials for 2010–2014 years” by the National Academy of Sciences of Ukraine (NASU).

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Authors and Affiliations

  1. Department of Biosynthesis of Nucleic Acids, Institute of Molecular Biology and Genetics, National Academy of Sciences of Ukraine, Zabolotnogo Str. 150, Kiev, 03680, Ukraine

    Aleksei Stepanenko Ph.D. & Prof. Vadym Kavsan Ph.D.

Authors
  1. Aleksei Stepanenko Ph.D.
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  2. Prof. Vadym Kavsan Ph.D.
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Corresponding author

Correspondence to Aleksei Stepanenko Ph.D. .

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Editors and Affiliations

  1. Oxford, United Kingdom

    Alexandra Alvergne

  2. Oxford, United Kingdom

    Crispin Jenkinson

  3. Paris, France

    Charlotte Faurie

Glossary

Aneuploidy

Refers to a state of karyotype when whole chromosome(s) or parts of chromosome(s) are lost or supernumerary

Chromosome instability (CIN)

Is a high rate of genome changes of a given cell population (cell to cell variation). It implies a constant process of generation of numerical (loss or gain of whole chromosomes) and structural (loss of chromosome arm, translocations, amplifications, deletions, insertions) aneuploidy variants

Clonal chromosome aberration

Is an aberration found in two cells or more among at least 20 examined metaphases

Dysplasia

Is appearance of the tissue as disordered, with the increased number of immature cells, and great variability between cells

Evolutionary potential

Is a probability of cell population to persist, adapt, and survive the harsh microenvironment, intrinsic or extrinsic stresses

Genetic network of a cell

Includes the whole gene content, RNA, and protein expression and their interaction in space and time

Genetically engineered mouse cancer model

Is a model when a mouse genetic profile is altered such that one or several genes thought to be involved in tumourigenesis are mutated, deleted, or overexpressed

Hyperplasia

Is a condition when cell number increases due to hyperproliferation unbalanced by cell elimination that results to an increase in the amount/volume of a tissue/organ

Non-clonal chromosome aberration

Is an aberration found in only one cell among at least 20–50 examined metaphases

Orthotopic xenograft

Is the transplantation of a primary human tumour mass or the injection of human tumour cell line into a mouse tissue from which a tumour mass/cell line naturally originated

Transcriptome

Is the complete set of mRNA, rRNA, tRNA, and other non-coding RNA transcripts produced by the genome of a cell or a population of cells at any given time

Transgene

Is a foreign gene that has been deliberately transferred into genome of a cell/an organism by the genetic engineering techniques

Transgene-negative tumours

Are tumours formed by cells, which lost a transgene that endowed advantageous traits and accelerated propagation

Somatic evolution

Is the accumulation of heritable (through mitosis) variations such as mutations, epigenetic changes, and sporadic aneuploidy in somatic cells within a body during a lifetime

Stochastic nature of cancer evolution

Implies that cancer is mainly driven by random, non-clonal, and transitional genome alterations, and these dynamic genome changes are neither shared by cells of the same tumour nor by the different tumours

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Stepanenko, A., Kavsan, V. (2016). Why Chemotherapy Does Not Work: Cancer Genome Evolution and the Illusion of Oncogene Addiction. In: Alvergne, A., Jenkinson, C., Faurie, C. (eds) Evolutionary Thinking in Medicine. Advances in the Evolutionary Analysis of Human Behaviour. Springer, Cham. https://doi.org/10.1007/978-3-319-29716-3_13

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  • DOI: https://doi.org/10.1007/978-3-319-29716-3_13

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