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DNA replication during acute MEK inhibition drives acquisition of resistance through amplification of the BRAF oncogene

View ORCID ProfilePrasanna Channathodiyil, View ORCID ProfileAnne Segonds-Pichon, Paul D. Smith, View ORCID ProfileSimon J. Cook, View ORCID ProfileJonathan Houseley
doi: https://doi.org/10.1101/2021.03.23.436572
Prasanna Channathodiyil
1Epigenetics Programme, Babraham Institute, Cambridge, UK
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Anne Segonds-Pichon
3Babraham Bioinformatics, Babraham Institute, Cambridge, UK
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Paul D. Smith
4Oncology R&D, AstraZeneca CRUK Cambridge Institute, Cambridge, UK
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Simon J. Cook
5Signalling programme, Babraham Institute, Cambridge, UK
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Jonathan Houseley
1Epigenetics Programme, Babraham Institute, Cambridge, UK
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  • For correspondence: jon.houseley@babraham.ac.uk
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Abstract

Mutations and gene amplifications that confer drug resistance emerge frequently during chemotherapy, but their mechanism and timing is poorly understood. Here, we investigate BRAFV600E amplification events that underlie resistance to the MEK inhibitor selumetinib (AZD6244/ARRY-142886) in COLO205 cells. We find that de novo focal BRAF amplification is the primary path to resistance irrespective of pre-existing amplifications. Although selumetinib causes long-term G1 arrest, we observe that cells stochastically re-enter the cell cycle during treatment without reactivation of ERK1/2 or induction of a normal proliferative gene expression programme. Genes encoding DNA replication and repair factors are downregulated during G1 arrest, but many are transiently induced when cells escape arrest and enter S and G2. Nonetheless, mRNAs encoding key DNA replication factors including the MCM replicative helicase complex, PCNA and TIPIN remain at very low abundance, which likely explains previous reports of replication stress and mutagenesis under long-term RAF-MEK-ERK1/2 pathway inhibition. To test the hypothesis that DNA replication in drug promotes de novo BRAF amplification, we exploited the combination of palbociclib and selumetinib to reinforce the G1 arrest. Using a palbociclib dose that suppresses cell cycle entry during selumetinib treatment but not during normal proliferation, we show that combined treatment robustly delays the emergence of drug resistant colonies. Our results demonstrate that acquisition of MEK inhibitor resistance can occur through de novo gene amplification events resulting from DNA replication in drug, and is suppressed by drug combinations that impede cell cycle entry.

Competing Interest Statement

PDS is a paid employee and shareholder of AstraZeneca plc. The remaining authors declare no conflicts of interest.

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 4.0 International license.
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Posted March 23, 2021.
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DNA replication during acute MEK inhibition drives acquisition of resistance through amplification of the BRAF oncogene
Prasanna Channathodiyil, Anne Segonds-Pichon, Paul D. Smith, Simon J. Cook, Jonathan Houseley
bioRxiv 2021.03.23.436572; doi: https://doi.org/10.1101/2021.03.23.436572
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DNA replication during acute MEK inhibition drives acquisition of resistance through amplification of the BRAF oncogene
Prasanna Channathodiyil, Anne Segonds-Pichon, Paul D. Smith, Simon J. Cook, Jonathan Houseley
bioRxiv 2021.03.23.436572; doi: https://doi.org/10.1101/2021.03.23.436572

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