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 Gassman

doi:10.20517/cdr.2020.73

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

Cancer Drug Resist. 2020 Dec 5;3(4):980-991. doi: 10.20517/cdr.2020.73. eCollection 2020.

Authors

Kevin J Lee^{1

2}, Griffin Wright^{1

2}, Hannah Bryant³, Leigh Ann Wiggins³, Michele Schuler^{3

4}, Natalie R Gassman^{1

2}

Affiliations

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.

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.

Keywords: CHK1; Triple negative breast cancer; apoptosis; drug resistance; epidermal growth factor receptor; mitogenic signaling; replication.