Related Experiment Video

Updated: Aug 17, 2026

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors
12:40

A Method for Screening and Validation of Resistant Mutations Against Kinase Inhibitors

Published on: December 7, 2014

A role for K-ras in conferring resistance to the MEK inhibitor, CI-1040

Yuli Wang1, Keri Van Becelaere, Ping Jiang

  • 1Molecular Sciences and Technologies, Pfizer Global Research and Development, Ann Arbor Laboratories, 2800 Plymouth Road, Ann Arbor, MI 48105, USA. yuli.wang@pfizer.com

Neoplasia (New York, N.Y.)
|June 22, 2005
PubMed

Insights

Tumor cells developed resistance to the MEK inhibitor CI-1040. This resistance is linked to increased K-ras expression, a key component of the MAP kinase pathway, potentially explaining how cancer cells overcome MEK-targeted therapies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • PD184352/CI-1040 is a selective MEK1/2 inhibitor and the first MEK-targeted agent in clinical trials.
  • Understanding resistance mechanisms to targeted therapies is crucial for effective cancer treatment.

Purpose of the Study:

  • To characterize the molecular mechanisms of CI-1040 resistance in a murine colon 26 (C26) carcinoma cell line.
  • To investigate the role of K-ras in conferring resistance to MEK inhibition.

Main Methods:

  • Development of a CI-1040 resistant C26 cell line (C26/CI-1040r).
  • Assays for cell growth, soft agar colony formation, and apoptosis induction.
  • Analysis of K-ras expression and its functional role in resistance via transfection.
  • Measurement of phosphorylated ERK1/2 levels.

Main Results:

  • C26/CI-1040r cells exhibited ~100-fold resistance to CI-1040 compared to parental cells.
  • Resistant cells showed reduced sensitivity to CI-1040-induced apoptosis.
  • Significantly elevated K-ras expression was observed in resistant cells.
  • Transfection of K-ras into parental cells conferred CI-1040 resistance and increased phosphorylated ERK1/2 levels.

Conclusions:

  • Increased activated K-ras expression is a key mechanism driving resistance to MEK inhibition.
  • This finding provides insight into how tumor cells overcome MAP kinase pathway blockade.
  • Identifying resistance mechanisms can inform future therapeutic strategies against MEK-targeted agents.

More Related Videos

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods07:49

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods

Published on: July 17, 2019

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...
The Ras Gene02:38

The Ras Gene

The Ras-gene-encoded proteins are regulators of signaling pathways controlling cell proliferation, differentiation, or cell survival. The Ras-gene family in humans constitutes three primary members—the HRas, NRas, and KRas. These genes code for four functionally distinct yet closely related proteins—the HRas, NRas, KRas4A, and KRas4B. The involvement of mutant Ras genes in human cancer was first discovered in 1982 and is among the most common causes of human tumorigenesis.
Ras is a superfamily...
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...
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...
Small GTPases - Ras and Rho01:24

Small GTPases - Ras and Rho

Ras and Rho are small monomeric GTPases that act downstream of receptor tyrosine kinase (RTK) and regulate various cellular processes. These GTPases switch between active and inactive states by binding to guanine nucleotides.
Three regulatory proteins control their activity:
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...