Related Experiment Video

Updated: May 21, 2026

Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures
07:48

Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures

Published on: December 26, 2016

Targeting the FOXO1/KLF6 axis regulates EGFR signaling and treatment response

Jaya Sangodkar1, Neil S Dhawan, Heather Melville

  • 1Department of Genetics and Genomic Sciences, Mount Sinai School of Medicine, New York, NY, USA.

The Journal of Clinical Investigation
|June 2, 2012
PubMed

Insights

Researchers discovered a new signaling pathway involving Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) that regulates cancer growth. An existing drug, trifluoperazine hydrochloride (TFP), can overcome resistance to EGFR-targeted therapies in lung cancer.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Genetics

Background:

  • Epidermal growth factor receptor (EGFR) activation drives cancer progression and is a target for anti-cancer therapies.
  • Resistance to EGFR-targeted therapies, often mediated by AKT signaling, limits treatment efficacy.
  • Understanding downstream mediators of EGFR signaling is crucial for developing new therapies for resistant cancers.

Purpose of the Study:

  • To identify novel molecular mechanisms regulating EGFR signaling and resistance to anti-EGFR therapies.
  • To investigate the role of Krüppel-like factor 6 (KLF6) and forkhead box O1 (FOXO1) in EGFR signaling.
  • To evaluate the potential of FDA-approved drugs to overcome resistance to EGFR-targeted therapies.

Main Methods:

  • Identification of a transcriptional network involving KLF6 and FOXO1 in cell culture and in vivo models.
  • Assessment of trifluoperazine hydrochloride (TFP) effects on EGFR signaling and drug resistance.
  • Utilized lung adenocarcinoma cell culture and xenograft models.

Main Results:

  • A novel transcriptional network involving KLF6 and FOXO1 was identified, negatively regulating EGFR signaling.
  • Trifluoperazine hydrochloride (TFP), by inhibiting FOXO1 nuclear export, restored sensitivity to erlotinib in AKT-driven resistance models.
  • The KLF6/FOXO1 signaling cascade was modulated by TFP, overcoming erlotinib resistance.

Conclusions:

  • A new transcriptional network regulating oncogenic EGFR signaling has been defined.
  • FDA-approved trifluoperazine hydrochloride (TFP) can restore sensitivity to anti-EGFR therapies in metastatic lung adenocarcinoma.
  • Targeting the KLF6/FOXO1 pathway presents a potential strategy for treating resistant lung cancer.

More Related Videos

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids08:52

Profiling Sensitivity to Targeted Therapies in EGFR-Mutant NSCLC Patient-Derived Organoids

Published on: November 22, 2021

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib09:38

Establishment and Characterization of Three Afatinib-resistant Lung Adenocarcinoma PC-9 Cell Lines Developed with Increasing Doses of Afatinib

Published on: June 26, 2019

Related Concept Videos

Mitogens and the Cell Cycle02:38

Mitogens and the Cell Cycle

Mitogens and their receptors play a crucial role in controlling the progression of the cell cycle. However, the loss of mitogenic control over cell division leads to tumor formation. Therefore, mitogens and mitogen receptors play an important role in cancer research. For instance, the epidermal growth factor (EGF) - a type of mitogen and its transmembrane receptor (EGFR), decides the fate of the cell's proliferation. When EGF binds to EGFR, a member of the ErbB family of tyrosine kinase...
Regulation of Angiogenesis and Blood Supply01:24

Regulation of Angiogenesis and Blood Supply

Rapidly dividing tumors, embryos, and wounded tissues require more oxygen than usual, lowering the oxygen concentration in the blood. At low oxygen or hypoxic conditions, an oxygen-sensitive transcription factor called the hypoxia-inducible factor 1 or HIF1 is activated. HIF1 is a dimeric protein of alpha (ɑ) and beta (β) subunits.  Under optimal oxygen conditions, HIF1β is present in the nucleus while HIF1ɑ remains in the cytosol. HIF1ɑ is hydroxylated by prolyl hydroxylase and factor...
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...
Receptor Downregulation in MVBs01:15

Receptor Downregulation in MVBs

Multivesicular bodies (MVBs) are mature endosomes that sort ubiquitinated proteins and then fuse with lysosomes to degrade the sorted proteins. Epidermal growth factor (EGF) and its receptor (EGFR) form a complex that can be internalized through endocytosis, sorted into an MVB, and later degraded.
The EGFR can initiate signaling pathways that  lead to cell proliferation, migration, and differentiation. Overexpression of EGFR  stimulates cells to proliferate. Excessive  EGFR activation may...
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...