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Lee et al. Cancer Drug Resist 2020;3:980-91 Cancer
DOI: 10.20517/cdr.2020.73 Drug Resistance

Original Article Open Access

EGFR signaling promotes resistance to CHK1
inhibitor prexasertib in triple negative breast cancer

Kevin J. Lee , Griffin Wright , Hannah Bryant , Leigh Ann Wiggins , Michele Schuler , Natalie R.
3
3
3,4
1,2
1,2
Gassman 1,2
1 Department of Physiology and Cell Biology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
2 Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
3 Department of Comparative Medicine, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
4 Department of Microbiology and Immunology, University of South Alabama College of Medicine, Mobile, AL 36688, USA.
Correspondence to: Dr. Natalie R. Gassman, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
E-mail: nrgassman@health.southalabama.edu
How to cite this article: Lee KJ, Wright G, Bryant H, Wiggins LA, Schuler M, Gassman NR. EGFR signaling promotes resistance
to CHK1 inhibitor prexasertib in triple negative breast cancer. Cancer Drug Resist 2020;3:980-91.
http://dx.doi.org/10.20517/cdr.2020.73
Received: 1 Sep 2020 First Decision: 19 Oct 2020 Revised: 20 Oct 2020 Accepted: 2 Nov 2020 Available online: 5 Dec 2020

Academic Editor: Godefridus J. Peters Copy Editor: Cai-Hong Wang Production Editor: Jing Yu

Abstract
Aim: Innate resistance to the CHK1 inhibitor prexasertib has been described, but resistance mechanisms are not
understood. We aimed to determine the role epidermal growth factor receptor (EGFR) plays in innate resistance to
prexasertib in triple negative breast cancer (TNBC).

Methods: Using a panel of pre-clinical TNBC cell lines, we measured the sensitivity to prexasertib. We examined
the effect activation of EGFR had on prexasertib sensitivity. We measured the synergy of dual blockade of EGFR
with erlotinib and CHK1 with prexasertib in TNBC cell lines and xenografts.

Results: EGFR overexpression and activation increased resistance to CHK1 inhibition by prexasertib. EGFR
promoted the phosphorylation of BCL2-associated agonist of cell death (BAD), inactivating its pro-apoptotic
functions. Inhibition of EGFR reversed BAD phosphorylation, increasing sensitivity to prexasertib.

Conclusion: The use of prexasertib as a monotherapy in TNBC has been limited due to modest clinical responses.
We demonstrated that EGFR activation contributes to innate resistance to prexasertib in TNBC and potentially
other cancers. EGFR expression status should be considered in clinical trials examining prexasertib’s use as a
monotherapy or combination therapy.

© The Author(s) 2020. Open Access This article is licensed under a Creative Commons Attribution 4.0
International License (https://creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
sharing, adaptation, distribution and reproduction in any medium or format, for any purpose, even commercially, as long
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and indicate if changes were made.

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