Related Experiment Video

Updated: Oct 12, 2025

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down
08:59

Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down

Published on: December 11, 2017

7.3K

HER2 + breast cancers evade anti-HER2 therapy via a switch in driver pathway

Alison E Smith1,2, Emanuela Ferraro1,3, Anton Safonov1,3

  • 1Human Oncology and Pathogenesis Program (HOPP), Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA.

Nature Communications
|November 19, 2021
PubMed

Insights

Genetic alterations activating MEK/ERK signaling drive resistance to HER2-targeted therapies in metastatic breast cancer. Targeting this pathway with MEK/ERK inhibitors offers a potential strategy to overcome treatment resistance.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • HER2-amplified breast cancer treatment relies on HER2 inhibition.
  • Resistance to HER2-targeted therapies is a significant clinical challenge, especially in metastatic settings.
  • The specific downstream signaling pathways driving this resistance remain incompletely understood.

Purpose of the Study:

  • To identify genetic alterations and signaling pathways that confer resistance to HER2 inhibition in metastatic breast cancer.
  • To investigate the mechanistic basis of resistance and identify potential therapeutic vulnerabilities.

Main Methods:

  • Genomic profiling of 733 HER2-amplified breast cancer samples.
  • Analysis of somatic alterations associated with progression-free survival on anti-HER2 therapy.
  • Functional studies to assess resistance mechanisms and drug sensitivity.

Main Results:

  • Somatic alterations promoting MEK/ERK signaling (e.g., NF1 loss, ERBB2 mutations) were enriched in metastatic tumors resistant to anti-HER2 therapy.
  • These alterations conferred resistance to FDA-approved HER2 kinase inhibitors (tucatinib, neratinib).
  • Resistant tumors exhibited reduced AKT dependence and increased sensitivity to MEK/ERK inhibition, driven by MEK-dependent CDK2 activation.

Conclusions:

  • Genetic activation of the MAPK pathway is a common mechanism of resistance to HER2-targeted therapies.
  • This resistance can be overcome by targeting the MEK/ERK pathway.
  • MEK/ERK inhibitors represent a promising therapeutic strategy for patients with resistant HER2-amplified breast cancer.

More Related Videos

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?14:20

Polymalic Acid-based Nano Biopolymers for Targeting of Multiple Tumor Markers: An Opportunity for Personalized Medicine?

Published on: June 13, 2014

16.8K
Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery13:19

Quantifying Antibody-Dependent Cellular Cytotoxicity in a Tumor Spheroid Model: Application for Drug Discovery

Published on: April 26, 2024

3.0K

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...
7.9K
Adaptive Mechanisms in Cancer Cells02:53

Adaptive Mechanisms in Cancer Cells

Cancer cells accumulate genetic changes at an abnormally rapid rate due to the defects in the DNA repair mechanisms. From an evolutionary perspective, such genetic instability is advantageous for cancer development. Mutant cell lines accumulate a series of beneficial mutations that contribute to their progression into cancer.
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
6.0K
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...
3.4K
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...
7.1K
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...
5.2K
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...
3.9K