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Review
. 2020 Apr 13;37(4):471-484.
doi: 10.1016/j.ccell.2020.03.007.

Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance

Andriy Marusyk  1 , Michalina Janiszewska  2 , Kornelia Polyak  3
Affiliations
Review

Intratumor Heterogeneity: The Rosetta Stone of Therapy Resistance

Andriy Marusyk et al. Cancer Cell. .

Abstract

Advances in our understanding of molecular mechanisms of tumorigenesis have translated into knowledge-based therapies directed against specific oncogenic signaling targets. These therapies often induce dramatic responses in susceptible tumors. Unfortunately, most advanced cancers, including those with robust initial responses, eventually acquire resistance to targeted therapies and relapse. Even though immune-based therapies are more likely to achieve complete cures, acquired resistance remains an obstacle to their success as well. Acquired resistance is the direct consequence of pre-existing intratumor heterogeneity and ongoing diversification during therapy, which enables some tumor cells to survive treatment and facilitates the development of new therapy-resistant phenotypes. In this review, we discuss the sources of intratumor heterogeneity and approaches to capture and account for it during clinical decision making. Finally, we outline potential strategies to improve therapeutic outcomes by directly targeting intratumor heterogeneity.

Keywords: cancer; heterogeneity; therapeutic resistance.

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Conflict of interest statement

Declaration of Interests K.P. is a member of the scientific advisory boards of Farcast Biosciences and Acrivon Therapeutics.

Figures

Figure 1.
Figure 1.. Sources of Intratumor heterogeneity.
Intratumor heterogeneity represents integration of inputs from genetic, phenotypic, and microenvironmental heterogeneity, in turn increasing the odds of both pre-existence of tolerant and resistant subpopulations, and the ability to evolve new adaptations.
Figure 2.
Figure 2.. Microenvironmental heterogeneity.
In normal tissues (such as normal breast) most epithelial cells experience similar concentrations of nutrients, oxygen, and growth factors. However, structural disorganization of epithelia, stroma, and vasculature leads to significant inequality in concentrations of these factors (one factor is illustrated). Further, differences in diffusion and consumption rates of different factors combinatorialy increase variability in microenvironmental cues directly influencing phenotypic heterogeneity and creating distinct selection forces.
Figure 3.
Figure 3.. Evolution of therapeutic resistance.
Heterogeneous primary tumors likely contain subpopulations of cancer cells with pre-existing resistance to therapy due to genetic or epigenetic mechanisms. Genetically resistant cancer cells can also outgrow from epigenetically plastic persisters in part due to therapy-induced alterations. Interaction with the microenvironment also contributes to phenotypic heterogeneity and associated therapeutic resistance within tumors. In most advanced-stage tumors both genetic and epigenetic resistance likely to be present leading to multiple different resistance mechanisms.
Figure 4.
Figure 4.. Optimal therapies for heterogeneous tumors.
The effective treatment of heterogeneous tumors requires optimized therapy to minimize the evolution of therapeutic resistance. There are three general approaches by which this can be achieved: (1) combination therapies targeting different tumor subpopulations, different dependencies, or both cell-autonomous and non-cell-autonomous functions; (2) therapies combining tumor-targeting agents with compounds that reduce ITH such as HDAC or BET inhibitors; and (3) adaptive therapy when ITH is maintained and the competition of drug-resistant and drug-sensitive cells is limited by alternating therapy and no treatment.
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