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Dark selection for JAK/STAT-inhibitor resistance in chronic myelomonocytic leukemia

Artem Kaznatcheev, David Robert Grimes, Robert Vander Velde, Vincent Cannataro, Etienne Baratchart, Andrew Dhawan, Lin Liu, Daria Myroshnychenko, Jake P. Taylor-King, Nara Yoon, Eric Padron, Andriy Marusyk, David Basanta
doi: https://doi.org/10.1101/211151
Artem Kaznatcheev
1Department of Computer Science, University of Oxford, Oxford, UK
2Department of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, OH, USA
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David Robert Grimes
3Advanced Interdisciplinary Radiation Research, Queen’s University Belfast, UK
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Robert Vander Velde
4Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
5Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, FL, USA
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Vincent Cannataro
6Department of Biostatistics, Yale School of Public Health, Yale University, New Haven, CT, USA
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Etienne Baratchart
7Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Andrew Dhawan
2Department of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, OH, USA
8Department of Oncology, University of Oxford, Oxford, UK
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Lin Liu
9Department of Biostatistics, Harvard T.H. Chan School of Public Health, Cambridge, MA, USA
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Daria Myroshnychenko
5Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, FL, USA
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Jake P. Taylor-King
7Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
10Mathematical Institute, University of Oxford, Oxford, UK
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Nara Yoon
2Department of Translational Hematology & Oncology Research, Cleveland Clinic, Cleveland, OH, USA
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Eric Padron
11Department of Malignant Hematology, Moffitt Cancer Center, Tampa, FL, USA
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Andriy Marusyk
5Department of Cancer Imaging and Metabolism, Moffitt Cancer Center, Tampa, FL, USA
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David Basanta
7Department of Integrated Mathematical Oncology, Moffitt Cancer Center, Tampa, FL, USA
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Abstract

Acquired therapy resistance to cancer treatment is a common and serious clinical problem. The classic U-shape model for the emergence of resistance supposes that: (1) treatment changes the selective pressure on the treatment-naive tumour; (2) this shifting pressure creates a proliferative or survival difference between sensitive cancer cells and either an existing or de novo mutant; (3) the resistant cells then out-compete the sensitive cells and – if further interventions (like drug holidays or new drugs or dosage changes) are not pursued – take over the tumour: returning it to a state dangerous to the patient. The emergence of ruxolitinib resistance in chronic myelomonocytic leukemia (CMML) seems to challenge the classic model: we see the global properties of resistance, but not the drastic change in clonal architecture expected with the selection bottleneck. To study this, we explore three population-level models as alternatives to the classic model of resistance. These three effective models are designed in such a way that they are distinguishable based on limited experimental data on the time-progression of resistance in CMML. We also propose a candidate reductive implementation of the proximal cause of resistance to ground these effective theories. With these reductive implementations in mind, we also explore the impact of oxygen diffusion and spatial structure more generally on the dynamics of CMML in the bone marrow concluding that, even small fluctuations in oxygen availability can seriously impact the efficacy of ruxolitinib. Finally, we look at the ability of spatially distributed cytokine signaling feedback loops to produce a relapse in symptoms similar to what we observe in the clinic.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 30, 2017.
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Dark selection for JAK/STAT-inhibitor resistance in chronic myelomonocytic leukemia
Artem Kaznatcheev, David Robert Grimes, Robert Vander Velde, Vincent Cannataro, Etienne Baratchart, Andrew Dhawan, Lin Liu, Daria Myroshnychenko, Jake P. Taylor-King, Nara Yoon, Eric Padron, Andriy Marusyk, David Basanta
bioRxiv 211151; doi: https://doi.org/10.1101/211151
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Dark selection for JAK/STAT-inhibitor resistance in chronic myelomonocytic leukemia
Artem Kaznatcheev, David Robert Grimes, Robert Vander Velde, Vincent Cannataro, Etienne Baratchart, Andrew Dhawan, Lin Liu, Daria Myroshnychenko, Jake P. Taylor-King, Nara Yoon, Eric Padron, Andriy Marusyk, David Basanta
bioRxiv 211151; doi: https://doi.org/10.1101/211151

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