Related Experiment Video

Updated: May 12, 2026

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity
09:32

Drug-Induced Senescence in Liver Cells Promotes M2 Macrophage Polarization: Implications for Tyrosine Kinase Inhibitor-Associated Hepatotoxicity

Published on: October 17, 2025

MEK inhibition increases lapatinib sensitivity via modulation of FOXM1

S S Gayle1, R C Castellino, M C Buss

  • 1Molecular & Systems Pharmacology Program, Graduate Division of Biological and Biomedical Sciences, Emory University, Atlanta, GA 30322, USA.

Current Medicinal Chemistry
|March 28, 2013
PubMed

Insights

MEK inhibition combined with lapatinib overcomes resistance in HER2-overexpressing breast cancer by reducing FOXM1 expression. This strategy improves therapeutic response in patients resistant to trastuzumab and lapatinib.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Trastuzumab is a standard therapy for HER2-overexpressing breast cancer, but resistance develops.
  • Lapatinib is used for trastuzumab-refractory disease, yet lapatinib resistance limits its efficacy.
  • Understanding resistance mechanisms is crucial for developing new therapeutic strategies.

Purpose of the Study:

  • To investigate the role of MEK/ERK signaling in lapatinib resistance.
  • To evaluate the efficacy of combined MEK inhibition and lapatinib treatment.
  • To identify downstream targets mediating resistance, such as FOXM1.

Main Methods:

  • Genetic and pharmacological inhibition of MEK/ERK signaling.
  • Cell viability assays (trypan blue exclusion).
  • Anchorage-independent growth assays.
  • Flow cytometry for cell cycle and apoptosis analysis.
  • Western blot, immunofluorescence, and immunohistochemistry.
  • In vivo tumor xenograft studies.

Main Results:

  • Combined MEK inhibition and lapatinib reduced phosphorylated ERK levels more effectively than single agents.
  • The combination treatment decreased nuclear FOXM1 expression.
  • Genetic knockdown of MEK enhanced lapatinib-induced cell cycle arrest and apoptosis.
  • Xenograft studies showed suppressed tumor growth and reduced FOXM1 in tumors treated with the combination therapy.

Conclusions:

  • FOXM1 contributes to lapatinib resistance downstream of MEK signaling.
  • Pharmacological MEK inhibition combined with lapatinib shows promise for overcoming resistance.
  • Further studies are warranted to explore MEK inhibition for improving lapatinib response in resistant HER2-positive breast cancer.

More Related Videos

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer06:51

Utilizing 18F-FDG PET/CT Imaging and Quantitative Histology to Measure Dynamic Changes in the Glucose Metabolism in Mouse Models of Lung Cancer

Published on: July 21, 2018

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor07:16

Monitoring Hippo Signaling Pathway Activity Using a Luciferase-based Large Tumor Suppressor (LATS) Biosensor

Published on: September 13, 2018

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway01:22

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin  (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1  (mTORC1) and mTOR complex 2  (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast,  mTORC2 consists of a rapamycin-insensitive companion...
Abnormal Proliferation02:23

Abnormal Proliferation

Under normal conditions, most adult cells remain in a non-proliferative state unless stimulated by internal or external factors to replace lost cells. Abnormal cell proliferation is a condition in which the cell's growth exceeds and is uncoordinated with normal cells. In such situations, cell division persists in the same excessive manner even after cessation of the stimuli, leading to persistent tumors. The tumor arises from the damaged cells that replicate to pass the damage to the daughter...
Interactions Between Signaling Pathways01:19

Interactions Between Signaling Pathways

Signaling cascades usually lack linearity. Multiple pathways interact and regulate one another, allowing cells to integrate and respond to diverse environmental stimuli.
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

The mammalian target of rapamycin or mTOR protein was discovered in 1994 due to its direct interaction with rapamycin. The protein gets its name from a yeast homolog called TOR. The mTOR protein complex in mammalian cells plays a major role in balancing anabolic processes such as the synthesis of proteins, lipids, and nucleotides and catabolic processes, such as autophagy in response to environmental cues, such as availability of nutrients and growth factors.
The mTOR pathway or the...
The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
Inhibition of Cdk Activity02:34

Inhibition of Cdk Activity

The orderly progression of the cell cycle depends on the activation of Cdk protein by binding to its cyclin partner. However, the cell cycle must be restricted when undergoing abnormal changes. Most cancers correlate to the deregulated cell cycle, and since Cdks are a central component of the cell cycle, Cdk inhibitors are extensively studied to develop anticancer agents. For instance, cyclin D associates with several Cdks, such as Cdk 4/6, to form an active complex. The cyclin D-Cdk4/6 complex...