Related Experiment Video

Updated: Jan 30, 2026

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model
09:29

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

Published on: March 20, 2020

18.9K

Overcoming acquired resistance to HSP90 inhibition by targeting JAK-STAT signalling in triple-negative breast cancer

Nuramalina H Mumin1, Neele Drobnitzky1, Agata Patel1

  • 1Department of Oncology, University of Oxford, Oxford, UK.

BMC Cancer
|January 26, 2019
PubMed
Abstract

Insights

Triple-negative breast cancer (TNBC) cells resistant to HSP90 inhibitors (HSP90i) show an activated JAK-STAT pathway. Combining JAK and HSP90 inhibition overcomes this resistance, offering a new targeted therapy approach for TNBC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Drug Discovery

Background:

  • Triple-negative breast cancer (TNBC) lacks effective therapies, necessitating novel targeted treatments.
  • Heat shock protein 90 (HSP90) inhibition is a promising strategy for TNBC, but resistance limits efficacy.
  • Understanding resistance mechanisms is crucial for developing effective HSP90 inhibitor (HSP90i) therapies.

Purpose of the Study:

  • To investigate the molecular basis of acquired resistance to HSP90 inhibitors in TNBC.
  • To identify potential therapeutic strategies to overcome HSP90i resistance in TNBC.

Main Methods:

  • Developed in vitro models of acquired resistance to HSP90i (ganetespib) using TNBC cells.
  • Utilized whole transcriptome profiling and a bioactive small molecule screen to analyze resistant cells.
  • Assessed the impact of combined JAK and HSP90 inhibition on apoptosis induction.

Main Results:

  • Acquired resistance to HSP90i was associated with the absence of client protein degradation and cell cycle arrest.
  • Resistant TNBC cells exhibited significant upregulation of the JAK-STAT signaling pathway, potentially via IL6 autocrine signaling.
  • Resistant cells showed selective sensitivity to JAK2 inhibition; combined JAK and HSP90 inhibition induced higher apoptosis.

Conclusions:

  • Upregulated JAK-STAT signaling is a key mechanism of acquired resistance to HSP90i in TNBC.
  • Combined inhibition of JAK-STAT signaling and HSP90 effectively overcomes acquired resistance.
  • This combination therapy holds promise for developing novel targeted treatments for TNBC patients.
Keywords:
Breast cancerGanetespibHSP90Heat shock proteinJAKResistanceSTATTNBCTriple-negative breast cancer

More Related Videos

Live Imaging to Study Microtubule Dynamic Instability in Taxane-resistant Breast Cancers06:02

Live Imaging to Study Microtubule Dynamic Instability in Taxane-resistant Breast Cancers

Published on: February 20, 2017

8.0K
Looking for Driver Pathways of Acquired Resistance to Targeted Therapy: Drug Resistant Subclone Generation and Sensitivity Restoring by Gene Knock-down08:59

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

Related Concept Videos

The JAK-STAT Signaling Pathway01:20

The JAK-STAT Signaling Pathway

Several cytokine receptors have tightly bound Janus kinase or JAK proteins attached at their cytosolic tail. Small signaling molecules such as cytokines, growth hormones, or prolactins bind to the cytokine receptors and initiate their dimerization. The dimerization brings the cytosolic JAKs together that trans-phosphorylate and activates each other. The activated JAKs now phosphorylate cytosolic tails of the cytokine receptors, which serve as binding sites for adaptor proteins such as  SH2...
12.5K
Negative Regulator Molecules01:23

Negative Regulator Molecules

Positive regulators allow a cell to advance through cell cycle checkpoints. Negative regulators have an equally important role as they terminate a cell’s progression through the cell cycle—or pause it—until the cell meets specific criteria.
38.5K
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...
3.8K
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...
8.9K
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...
4.8K
Feedback Inhibition00:46

Feedback Inhibition

Biochemical reactions are occurring constantly in cells, converting starting substances to different products, usually with the help of enzymes that speed the reactions. Without enzymes, it would take far too long for most reactions to occur to be useful to the cell!
57.1K