Inhibition of MCL-1 and MEK Overcomes MEK Inhibitor Resistance in Triple-Negative and Inflammatory Breast Cancers

Authors

Mohd Mughees
Moises Tacam
Alex W Tan
Mary Kathryn Pitner
Lakesla R Iles
Xiaoding Hu
Emilly S Villodre
Bisrat G Debeb
Takahiro Kogawa
Bora Lim
Rachel M Layman
Wendy A Woodward
Naoto T Ueno
Debu Tripathy
Savitri Krishnamurthy
Yuan Qi
Lajos Pusztai
Jian Wang
Varsha Gandhi
Geoffrey Bartholomeusz
Chandra Bartholomeusz

Language

English

Publication Date

9-2-2025

Journal

Molecular Cancer Therapeutics

DOI

10.1158/1535-7163.MCT-24-0593

PMID

40358476

PMCID

PMC12354021

PubMedCentral® Posted Date

3-2-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

The MAPK pathway can drive resistance in highly aggressive breast cancers. Our previous work showed that the MEK inhibitor (MEKi) AZD6244 (selumetinib) prevented lung metastasis in a breast cancer xenograft model. In clinical studies, MEKis as single agents have had only modest activity against solid tumors due to the onset of resistance. Using synthetic lethality siRNA screening, we identified myeloid cell leukemia-1 (MCL-1) as a potential contributor to AZD6244 resistance. We hypothesized that MCL-1 promotes MEKi resistance in highly aggressive breast cancers and that MCL-1 inhibition overcomes AZD6244 resistance. We established two AZD6244-resistant cell lines: MDA-MB-231-R (triple-negative breast cancer) and SUM149-R (triple-negative inflammatory breast cancer). These resistant cells were characterized with respect to different parameters, and a combination of an MCL-1 inhibitor (MCL-1i) together with an MEKi was evaluated in vitro and in vivo to overcome the acquired resistance. Compared with their respective parental cells, MDA-MB-231-R and SUM149-R cells showed increased proliferation, colony formation, stemness, anchorage-independent growth, and MCL-1 expression levels. MCL-1 knockdown in resistant cells decreased cell proliferation and colony formation, increased apoptosis, and was associated with high expression of the proapoptotic proteins PUMA, NOXA, BAK, and BAX. MEKi resistance was overcome when resistant cells were treated with MCL-1i and MEKi combined. In an in vivo mouse model, inhibition of MCL-1 restored sensitivity to AZD6244. Our results suggest that MCL-1 is a driver of MEKi resistance and that combining an MCL-1i with an MEKi warrants further investigation in triple-negative and triple-negative inflammatory breast cancer.

Keywords

Humans, Myeloid Cell Leukemia Sequence 1 Protein, Drug Resistance, Neoplasm, Triple Negative Breast Neoplasms, Female, Animals, Cell Line, Tumor, Mice, Xenograft Model Antitumor Assays, Protein Kinase Inhibitors, Inflammatory Breast Neoplasms, Benzimidazoles, Cell Proliferation, Apoptosis, Mitogen-Activated Protein Kinase Kinases, TNBC, IBC, MAPK pathway, MEK inhibitor resistance, MCL-1, combination therapy, targeted therapy

Published Open-Access

yes

Recommended Citation

Mughees, Mohd; Tacam, Moises; Tan, Alex W; et al., "Inhibition of MCL-1 and MEK Overcomes MEK Inhibitor Resistance in Triple-Negative and Inflammatory Breast Cancers" (2025). Faculty, Staff and Student Publications. 6150.
https://digitalcommons.library.tmc.edu/uthgsbs_docs/6150