Related Experiment Video

Updated: Jan 20, 2026

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

7.6K

HSP90/AXL/eIF4E-regulated unfolded protein response as an acquired vulnerability in drug-resistant KRAS-mutant lung

Haitang Yang1,2, Shun-Qing Liang1,2,3, Duo Xu1,2

  • 1Department of General Thoracic Surgery, Inselspital, Bern University Hospital, Bern, Switzerland.

Oncogenesis
|August 22, 2019
PubMed

Insights

Drug-resistant KRAS-mutant lung cancers develop vulnerabilities to therapies targeting endoplasmic reticulum stress. Blocking HSP90, AXL, eIF4E, or the unfolded protein response offers new treatment strategies.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Drug resistance and tumor heterogeneity pose significant challenges in treating KRAS-mutant lung cancers.
  • KRAS-mutant cancers are notoriously difficult to treat with targeted therapies and chemotherapy.

Purpose of the Study:

  • To investigate the molecular mechanisms underlying drug resistance in KRAS-mutant lung cancer.
  • To identify novel therapeutic vulnerabilities in resistant and heterogeneous KRAS-mutant lung tumors.

Main Methods:

  • Analysis of KRAS-mutant lung cancer cells resistant to pemetrexed (MTA) and trametinib.
  • Investigated dependencies on endoplasmic reticulum (ER) stress signaling, HSP90, AXL, eIF4E, and the unfolded protein response (UPR).
  • Evaluated synergistic effects of HSP90 inhibitors with MTA and trametinib.

Main Results:

  • Drug-resistant KRAS-mutant lung cancer cells exhibit dependency on ER stress signaling.
  • Resistant cells become susceptible to inhibitors of HSP90, AXL, eIF4E, and UPR.
  • Drug resistance involves hyperactive AXL/eIF4E, increased ER protein turnover, and adaptive UPR activation.
  • These vulnerabilities are also present in tumors with de novo intratumor heterogeneity.
  • HSP90 inhibitors synergize with MTA and trametinib, enhancing antitumor effects.

Conclusions:

  • Drug resistance and tumor heterogeneity in KRAS-mutant lung cancer create collateral vulnerabilities.
  • Targeting ER stress pathways (HSP90, AXL, eIF4E, UPR) represents a promising therapeutic strategy.
  • Combination therapy with HSP90 inhibitors, MTA, and trametinib shows potential for treating KRAS-mutant lung cancer.

More Related Videos

Exploring Biomolecular Interaction Between the Molecular Chaperone Hsp90 and Its Client Protein Kinase Cdc37 using Field-Effect Biosensing Technology09:39

Exploring Biomolecular Interaction Between the Molecular Chaperone Hsp90 and Its Client Protein Kinase Cdc37 using Field-Effect Biosensing Technology

Published on: March 31, 2022

3.7K
Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells08:47

Monitoring eIF4F Assembly by Measuring eIF4E-eIF4G Interaction in Live Cells

Published on: May 1, 2020

3.3K

Related Concept Videos

Regulation of the Unfolded Protein Response01:31

Regulation of the Unfolded Protein Response

Inositol-requiring kinase one or IRE1 is the most conserved eukaryotic unfolded protein response (UPR) receptor. It is a type I transmembrane protein kinase receptor with a distinctive site-specific RNase activity. As the binding mechanics of the misfolded proteins with the N-terminal domain of IRE-1 are unclear, three binding models — direct, indirect, and allosteric -- are proposed for receptor activation. Nevertheless, it is known that once a misfolded protein associates with IRE1, it...
2.9K
The Unfolded Protein Response01:37

The Unfolded Protein Response

The ER is the hub of protein synthesis in a cell. It has robust systems to quality control protein folding and also for degradation of terminally misfolded proteins. Under normal conditions, a small proportion of misfolded proteins that cannot be salvaged need to be transported to the cytoplasm by the ER-associated degradation or ERAD pathways. However, if the ERAD cannot handle the misfolded proteins, the cell activates the unfolded protein response or UPR to adjust the protein folding...
6.3K
Regulated Protein Degradation02:58

Regulated Protein Degradation

It is vital to regulate the activity of enzymatic as well as non-enzymatic proteins inside the cell. This can be achieved either through creating a balance between their rate of synthesis and degradation or regulating the intrinsic activity of the protein. Both these regulation mechanisms play an essential role in the normal functioning of cells.
Protein degradation plays two important roles in the cells. It helps to protect cells from misfolded or damaged proteins before they lead to a...
8.8K
Regulated Protein Degradation02:58

Regulated Protein Degradation

3.1K
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

Proteins can undergo many types of post-translational modifications, often in response to changes in their environment. These modifications play an important role in the function and stability of these proteins. Covalently linked molecules include functional groups, such as methyl, acetyl, and phosphate groups, and also small proteins, such as ubiquitin. There are around 200 different types of covalent regulators that have been identified.
These groups modify specific amino acids in a protein....
8.7K
Covalently Linked Protein Regulators02:04

Covalently Linked Protein Regulators

2.0K