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Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance

View ORCID ProfileFabian Fröhlich, View ORCID ProfileLuca Gerosa, View ORCID ProfileJeremy Muhlich, View ORCID ProfilePeter K. Sorger
doi: https://doi.org/10.1101/2022.02.17.480899
Fabian Fröhlich
1Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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  • ORCID record for Fabian Fröhlich
Luca Gerosa
1Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
2Genentech, Inc., South San Francisco, CA 94080
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Jeremy Muhlich
1Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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Peter K. Sorger
1Laboratory of Systems Pharmacology, Department of Systems Biology, Harvard Medical School, 200 Longwood Avenue, Boston, MA 02115, USA
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  • For correspondence: psorger@hms.harvard.edu
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ABSTRACT

BRAFV600E is prototypical of oncogenic mutations that can be targeted therapeutically and treatment of BRAF-mutant melanomas with RAF and MEK inhibitors results in rapid tumor regression. However, drug-induced rewiring causes BRAFV600E melanoma cells to rapidly acquire a drug-adapted state. In patients this is thought to promote acquisition or selection for resistance mutations and disease recurrence. In this paper we use an energy-based implementation of ordinary differential equations in combination with proteomic, transcriptomic and imaging data from melanoma cells, to model the precise mechanisms responsible for adaptive rewiring. We demonstrate the presence of two parallel MAPK (RAF-MEK-ERK kinase) reaction channels in BRAFV600E melanoma cells that are differentially sensitive to RAF and MEK inhibitors. This arises from differences in protein oligomerization and allosteric regulation induced by oncogenic mutations and drug binding. As a result, the RAS-regulated MAPK channel can be active under conditions in which the BRAFV600E-driven channel is fully inhibited. Causal tracing demonstrates that this provides a sufficient quantitative explanation for initial and acquired responses to multiple different RAF and MEK inhibitors individually and in combination.

Highlights

  • A thermodynamic framework enables structure-based description of allosteric interactions in the EGFR and MAPK pathways

  • Causal decomposition of efficacy of targeted drugs elucidates rewiring of MAPK channels

  • Model-based extrapolation from type I½ RAF inhibitors to type II RAF inhibitors

  • A unified mechanistic explanation for adaptive and genetic resistance across BRAF-cancers

Competing Interest Statement

PKS is a member of the SAB or Board of Directors of Glencoe Software, Applied Biomath, and RareCyte Inc. and has equity in these companies; PKS is also a member of the SAB of NanoString and a consultant for Montai Health and Merck. LG is currently an employee of Genentech. PKS and LG declare that none of these relationships are directly or indirectly related to the content of this manuscript.

Footnotes

  • https://github.com/labsyspharm/marm2-supplement

Copyright 
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-ND 4.0 International license.
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Posted February 18, 2022.
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Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance
Fabian Fröhlich, Luca Gerosa, Jeremy Muhlich, Peter K. Sorger
bioRxiv 2022.02.17.480899; doi: https://doi.org/10.1101/2022.02.17.480899
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Mechanistic model of MAPK signaling reveals how allostery and rewiring contribute to drug resistance
Fabian Fröhlich, Luca Gerosa, Jeremy Muhlich, Peter K. Sorger
bioRxiv 2022.02.17.480899; doi: https://doi.org/10.1101/2022.02.17.480899

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