Related Experiment Video

Updated: Jun 3, 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

Resistance to MEK inhibitors: should we co-target upstream?

Poulikos I Poulikakos1, David B Solit

  • 11Program in Molecular Pharmacology and Chemistry, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.

Science Signaling
|March 31, 2011
PubMed

Insights

Aberrant activation of the ERK pathway drives cancer. MEK inhibitor resistance occurs due to upstream driver amplification, but combining RAF and MEK inhibitors may overcome this in BRAF-mutant tumors.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Signaling

Background:

  • Aberrant activation of the Extracellular signal-Regulated Kinase (ERK) pathway is a hallmark of human cancers.
  • The ERK pathway, a three-tiered kinase module (RAF, MEK, ERK), is crucial for cell growth and survival.
  • Targeting the ERK pathway with inhibitors is a promising anticancer strategy, but drug resistance is a significant challenge.

Purpose of the Study:

  • To investigate the mechanisms of resistance to MEK inhibitors in ERK pathway-driven cancers.
  • To explore therapeutic strategies to overcome MEK inhibitor resistance.
  • To provide a mechanistic rationale for combining RAF and MEK inhibitors in cancer treatment.

Main Methods:

  • Analysis of ERK pathway signaling dynamics in cancer cells.
  • Investigating the role of upstream oncogenic drivers (BRAF, KRAS) in drug resistance.
  • Evaluating the efficacy of combined RAF and MEK inhibition in preclinical models.

Main Results:

  • MEK inhibitor resistance is mediated by amplification of upstream oncogenic drivers like BRAF or KRAS.
  • Increased driver abundance leads to restored ERK pathway activity despite MEK inhibition.
  • Concurrent inhibition of RAF and MEK demonstrates potential to delay or overcome resistance in BRAF-mutant cancers.

Conclusions:

  • Amplification of oncogenic drivers is a key mechanism of resistance to MEK inhibitors.
  • Combined RAF and MEK inhibition offers a rational approach to overcome resistance in BRAF-mutant cancers.
  • This study provides a mechanistic basis for clinical trials investigating combination therapies for ERK pathway-driven malignancies.

More Related Videos

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

Related Concept Videos

Targeted Cancer Therapies02:57

Targeted Cancer Therapies

The targeted cancer therapies, also known as “molecular targeted therapies,” take advantage of the molecular and genetic differences between the cancer cells and the normal cells. It needs a thorough understanding of the cancer cells to develop drugs that can target specific molecular aspects that drive the growth, progression, and spread of cancer cells without affecting the growth and survival of other normal cells in the body.
There are several types of targeted therapies against specific...
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...
Treatment Resistant Cancers02:56

Treatment Resistant Cancers

Cancer is the second leading cause of death in the United States. A cancer cell is genetically unstable and hence can mutate faster. They can also modify their microenvironment and escape immune surveillance. The difficulties in treating cancer are further compounded by the emergence of rapid resistance to anticancer drugs. The most common ways to attain resistance in cancer cells include alteration in drug transport and metabolism, modification of drug target, elevated DNA damage response, or...
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...
Combination Therapies and Personalized Medicine02:50

Combination Therapies and Personalized Medicine

Combining two or more treatment methods increases the life span of cancer patients while reducing damage to vital organs or tissue from the overuse of a single treatment. Combination therapy also targets different cancer-inducing pathways, thus reducing the chances of developing resistance to treatment.
The combination of the drug acetazolamide and sulforaphane is a good example of combination therapy to treat cancer. The cells in the interior of a large tumor often die due to the hypoxic and...