Related Experiment Video

Updated: Mar 20, 2026

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
07:42

Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays

Published on: September 19, 2018

8.4K

The Mitogen-Activated Protein Kinase Pathway Facilitates Resistance to the Src Inhibitor Dasatinib in Thyroid Cancer

Thomas C Beadnell1, Katie M Mishall1, Qiong Zhou1

  • 1Division of Endocrinology, Metabolism, and Diabetes, Department of Medicine, University of Colorado School of Medicine, Aurora, Colorado.

Molecular Cancer Therapeutics
|May 26, 2016
PubMed

Insights

Src inhibitors show limited efficacy in advanced thyroid cancer. Resistance mechanisms involve SRC mutations and MAPK pathway activation, suggesting combination therapies with MEK inhibitors could improve treatment outcomes.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Advanced thyroid cancer, including papillary and anaplastic types, is aggressive with limited therapeutic options.
  • c-SRC is a key mediator of thyroid cancer growth, invasion, and metastasis, making it a promising therapeutic target.
  • Clinical efficacy of Src inhibitors is often limited, necessitating research into resistance mechanisms and combination therapies.

Purpose of the Study:

  • To investigate resistance mechanisms to the Src inhibitor dasatinib in thyroid cancer.
  • To explore the role of MAPK pathway activation in dasatinib resistance.
  • To evaluate the efficacy of combination therapies involving dasatinib and MEK/ERK inhibitors.

Main Methods:

  • Generated four thyroid cancer cell lines with acquired resistance to dasatinib.
  • Analyzed for c-SRC gatekeeper mutations (T341M) in RAS-mutant lines and BRAF-mutant lines.
  • Assessed MAPK pathway activation and response to MEK1/2 inhibition.
  • Evaluated in vivo efficacy of MEK1/2 inhibition in a resistant cell line model.
  • Tested upfront combination therapy with dasatinib and MEK/ERK inhibitors.

Main Results:

  • RAS-mutant resistant cell lines acquired the c-SRC gatekeeper mutation (T341M), rendering Src signaling refractory to dasatinib.
  • BRAF-mutant resistant cell lines did not acquire the gatekeeper mutation.
  • MAPK pathway activation increased in all resistant cell lines, potentially via B-Raf and c-Raf dimerization.
  • MEK1/2 inhibition restored sensitivity to dasatinib in all resistant cell lines and overcame resistance in vivo.
  • Combined dasatinib and MEK1/2 or ERK1/2 inhibition demonstrated synergistic effects on growth inhibition and apoptosis induction.

Conclusions:

  • Acquisition of the c-SRC gatekeeper mutation and MAPK pathway signaling are key mechanisms of dasatinib resistance in thyroid cancer.
  • Combined inhibition strategies targeting Src and MAPK pathways offer a promising approach to overcome resistance and improve therapeutic outcomes in advanced thyroid cancer.

More Related Videos

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants07:38

Intracellular Phosphoflow Cytometry of Acute Myeloid Leukemia Patient-Derived Xenotransplants

Published on: June 6, 2025

900
Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence10:09

Methods for Evaluating the Role of c-Fos and Dusp1 in Oncogene Dependence

Published on: January 7, 2019

8.8K

Related Concept Videos

MAPK Signaling Cascades01:07

MAPK Signaling Cascades

Mitogen-activated protein kinase, or MAPK pathway, activates three sequential kinases to regulate cellular responses such as proliferation, differentiation, survival, and apoptosis. The canonical MAPK pathway starts with a mitogen or growth factor binding to an RTK. The activated RTKs stimulate Ras, which recruits Raf or MAP3 Kinase (MAPKKK), the first kinase of the MAPK signaling cascade. Raf further phosphorylates and activates MEK or MAP2 Kinases (MAPKK), which in turn phosphorylates MAP...
9.1K
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...
5.0K
mTOR Signaling and Cancer Progression03:03

mTOR Signaling and Cancer Progression

1.6K
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...
6.2K
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...
7.8K
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...
8.4K