Theoretical analysis reveals a role for RAF conformational autoinhibition in paradoxical activation

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Abstract

RAF kinase inhibitors can, under certain conditions, increase RAF kinase signaling. This process, which is commonly referred to as 'paradoxical activation' (PA), is incompletely understood. We use mathematical and computational modeling to investigate PA, and we derive rigorous analytical expressions that illuminate the underlying mechanism of this complex phenomenon. We find that conformational autoinhibition modulation by a RAF inhibitor could be sufficient to create PA. We find that experimental RAF-inhibitor drug dose response data that characterize PA across different types of RAF inhibitors are best explained by a model that includes RAF-inhibitor modulation of three properties: conformational autoinhibition, dimer affinity, and drug binding within the dimer (i.e., negative cooperativity). Overall, this work establishes conformational autoinhibition as a robust mechanism for RAF-inhibitor driven PA based solely on equilibrium dynamics of canonical interactions that comprise RAF signaling and inhibition.

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All data needed to evaluate the conclusions in the paper are present in the paper or the Supplementary Materials. All materials are available upon request from the corresponding author.

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Gaurav Mendiratta

Integrative Biology Laboratory, Salk Institute for Biological Studies, La Jolla, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0001-5091-348X
Edward Stites

Department of Laboratory Medicine, Yale University, New Haven, United States

For correspondence
edward.stites@yale.edu

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-3783-7336

Funding

National Institutes of Health (K22CA216318)

Edward Stites

National Institutes of Health (DP2AT011327)

Edward Stites

Melanoma Research Alliance (Young Investigator Award)

Edward Stites

Joe W. and Dorothy Dorsett Brown Foundation (N/A)

Edward Stites

Salk Institute for Biological Studies

Gaurav Mendiratta

Conrad Prebys Foundation (N/A)

Edward Stites

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.