Article in Molecular cancer therapeutics, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 2 papers.
0numbers the graph read from it
0cells of the map it votes in
2citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
2 · The registry
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
5 · Who and what money
Authors and funding
21 authors.
Mohd MugheesSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-5533-8135
Moises TacamSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-9292-1020
Alex W TanSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0001-6972-570X
Mary Kathryn PitnerSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0009-0004-7423-6072
Lakesla R IlesDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-6992-7910
Xiaoding HuSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-3144-1859
Emilly S VillodreSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-3092-7013
Bisrat G DebebSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-8227-2266
Takahiro KogawaDepartment of Advanced Medical Development, Cancer Institute Hospital of JFCR, Tokyo, Japan.ORCID 0000-0003-3730-6591
Bora LimSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-4182-6058
Rachel M LaymanMorgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-8663-0331
Wendy A WoodwardMorgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-7935-739X
Naoto T UenoSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-0166-7275
Debu TripathySection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-5711-2404
Savitri KrishnamurthyMorgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-9030-4136
Yuan QiBioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-9718-7593
Lajos PusztaiSection of Medical Oncology, Department of Medicine, Yale School of Medicine, Yale Cancer Center, New Haven, Connecticut.ORCID 0000-0001-9632-6686
Jian WangDepartment of Biostatistics, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0001-7104-0673
Varsha GandhiDepartment of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-3172-9166
Geoffrey BartholomeuszMorgan Welch Inflammatory Breast Cancer Clinic and Research Program, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-4622-4195
Chandra BartholomeuszSection of Translational Breast Cancer Research, Department of Breast Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, Texas.ORCID 0000-0002-5806-1557
Funding
Tumor Evolution and Metastasis ProgramP30CA016672 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI Fabien Delerue · 1985 to 2026
$290.8M
Development of Targeted Therapy for ERK Pathway in Breast CancerR00CA139006 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI BARTHOLOMEUSZ, CHANDRA · 2013 to 2015
$725k
Development of Targeted Therapy for ERK Pathway in Breast CancerK99CA139006 · NCI · UNIVERSITY OF TX MD ANDERSON CAN CTR · PI BARTHOLOMEUSZ, CHANDRA · 2009 to 2010
$230k
American Cancer Society (ACS) RSG-17-205-01 - TBGNational Cancer Institute (NCI) K99CA139006 and R00CA139006National Cancer Institute (NCI) P30CA016672NCI NIH HHS K99 CA139006NCI NIH HHS P30 CA016672NCI NIH HHS R00 CA139006
6 · The paper itself
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.
Indexed as
Drug Resistance, NeoplasmInflammatory Breast NeoplasmsMitogen-Activated Protein Kinase KinasesMyeloid Cell Leukemia Sequence 1 ProteinProtein Kinase InhibitorsTriple Negative Breast NeoplasmsAnimalsApoptosisBenzimidazolesCell Line, TumorCell ProliferationFemaleHumansMiceXenograft Model Antitumor AssaysAZD 6244BenzimidazolesMCL1 protein, humanMitogen-Activated Protein Kinase KinasesMyeloid Cell Leukemia Sequence 1 ProteinProtein Kinase Inhibitors
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.
Inhibition of MCL-1 and MEK Overcomes MEK Inhibitor Resistance in Triple-Negative and Inflammatory Breast Cancers. · full record | OpenQuestion