Related Experiment Video

Updated: Mar 22, 2026

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors

Next Generation Sequencing for the Detection of Actionable Mutations in Solid and Liquid Tumors

Published on: September 20, 2016

Triple-negative breast cancers with amplification of JAK2 at the 9p24 locus demonstrate JAK2-specific dependence

Justin M Balko¹, Luis J Schwarz², Na Luo²

¹Department of Medicine, Vanderbilt University, Nashville, TN 37232, USA. Department of Cancer Biology, Vanderbilt University, Nashville, TN 37232, USA. Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, TN 37232, USA. carlos.arteaga@vanderbilt.edu justin.balko@vanderbilt.edu.

Science Translational Medicine

|April 15, 2016

Abstract:

Amplifications at 9p24 have been identified in breast cancer and other malignancies, but the genes within this locus causally associated with oncogenicity or tumor progression remain unclear. Targeted next-generation sequencing of postchemotherapy triple-negative breast cancers (TNBCs) identified a group of 9p24-amplified tumors, which contained focal amplification of the Janus kinase 2 (JAK2) gene. These patients had markedly inferior recurrence-free and overall survival compared to patients with TNBC without JAK2 amplification. Detection of JAK2/9p24 amplifications was more common in chemotherapy-treated TNBCs than in untreated TNBCs or basal-like cancers, or in other breast cancer subtypes. Similar rates of JAK2 amplification were confirmed in patient-derived TNBC xenografts. In patients for whom longitudinal specimens were available, JAK2 amplification was selected for during neoadjuvant chemotherapy and eventual metastatic spread, suggesting a role in tumorigenicity and chemoresistance, phenotypes often attributed to a cancer stem cell-like cell population. In TNBC cell lines with JAK2 copy gains or amplification, specific inhibition of JAK2 signaling reduced mammosphere formation and cooperated with chemotherapy in reducing tumor growth in vivo. In these cells, inhibition of JAK1-signal transducer and activator of transcription 3 (STAT3) signaling had little effect or, in some cases, counteracted JAK2-specific inhibition. Collectively, these results suggest that JAK2-specific inhibitors are more efficacious than dual JAK1/2 inhibitors against JAK2-amplified TNBCs. Furthermore, JAK2 amplification is a potential biomarker for JAK2 dependence, which, in turn, can be used to select patients for clinical trials with JAK2 inhibitors.

Insights

Amplification of the Janus kinase 2 (JAK2) gene in triple-negative breast cancer (TNBC) is linked to poor survival and chemoresistance. JAK2 inhibitors show promise for treating these specific tumors.

Area of Science:

Oncology
Genetics
Molecular Biology

Background:

9p24 locus amplifications are observed in various cancers, but specific oncogenic drivers remain elusive.
Triple-negative breast cancer (TNBC) presents significant therapeutic challenges.
The role of specific genes within the 9p24 locus in TNBC progression is not well understood.

Purpose of the Study:

To investigate the role of Janus kinase 2 (JAK2) gene amplification in triple-negative breast cancer (TNBC).
To determine the clinical significance and therapeutic implications of JAK2 amplification in TNBC.
To evaluate the efficacy of JAK2-specific inhibitors in JAK2-amplified TNBC.

Main Methods:

Targeted next-generation sequencing of TNBC tumors, particularly post-chemotherapy samples.
Analysis of patient survival data (recurrence-free and overall survival).
In vitro studies using TNBC cell lines with JAK2 amplification, including mammosphere assays and drug sensitivity testing.
In vivo studies using patient-derived TNBC xenografts.

Main Results:

Focal amplification of the JAK2 gene was identified in a subset of 9p24-amplified TNBCs.
Patients with JAK2 amplification exhibited significantly worse recurrence-free and overall survival.
JAK2 amplification was found to be selected during chemotherapy and associated with metastatic spread, suggesting a role in tumorigenesis and chemoresistance.
Specific JAK2 inhibition reduced tumor growth in vitro and cooperated with chemotherapy in vivo.
JAK2-specific inhibitors demonstrated greater efficacy than dual JAK1/2 inhibitors in preclinical models.

Conclusions:

JAK2 amplification is a significant driver in a subset of TNBC, associated with poor prognosis and therapeutic resistance.
Targeting JAK2 signaling represents a promising therapeutic strategy for JAK2-amplified TNBC.
JAK2 amplification serves as a potential biomarker for identifying patients who may benefit from JAK2 inhibitor therapy.

Read full analysis

More Related Videos

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

Studying Triple Negative Breast Cancer Using Orthotopic Breast Cancer Model

Published on: March 20, 2020

Integration of Wet and Dry Bench Processes Optimizes Targeted Next-generation Sequencing of Low-quality and Low-quantity Tumor Biopsies

Integration of Wet and Dry Bench Processes Optimizes Targeted Next-generation Sequencing of Low-quality and Low-quantity Tumor Biopsies

Published on: April 11, 2016

Related Concept Videos

PI3K/mTOR/AKT Signaling Pathway

PI3K/mTOR/AKT Signaling Pathway

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that regulates growth, proliferation, and cell survival in response to hormones, growth factors, or nutrient availability. This kinase exists in two structurally and functionally distinct forms: mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The first form (mTORC1) is composed of a rapamycin-sensitive Raptor and proline-rich Akt substrate, PRAS40. In contrast, mTORC2 consists of a...

Cancer-Critical Genes II: Tumor Suppressor Genes

Cancer-Critical Genes II: Tumor Suppressor Genes

Genes usually encode proteins necessary for the proper functioning of a healthy cell. Mutations can often cause changes to the gene expression pattern, thereby altering the phenotype.
When the function of certain critical genes, especially those involved in cell cycle regulation and cell growth signaling cascades, gets disrupted, it upsets the cell cycle progression. Such cells with unchecked cell cycles start proliferating uncontrollably and eventually develop into tumors.
Such genes that act...

Cancer-Critical Genes II: Tumor Suppressor Genes

Cancer-Critical Genes II: Tumor Suppressor Genes

The JAK-STAT Signaling Pathway

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...

mTOR Signaling and Cancer Progression

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...

Targeted Cancer Therapies

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...

Articles linked to this work by shared authors, journal, and citation graph.

ERK1/2 Inhibitor Ulixertinib in Pan-cancer Patients with BRAF Fusions or Non-V600E/K Mutations: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol Z1L.

Clinical cancer research : an official journal of the American Association for Cancer Research·2026

Phase II Study of Adavosertib in Patients With Tumors Containing BRCA1 and BRCA2 Mutations: Results From the NCI-MATCH ECOG-ACRIN Cancer Research Group (EAY131) Subprotocol Z1I.

JCO precision oncology·2026

Impact of Race, Socioeconomic Status, and Clinicopathologic Features on Clinical Outcomes in Triple-Negative Breast Cancer in the ECOG-ACRIN EA1131 Trial.

JCO oncology advances·2026

Larotrectinib in Patients With Tumors With NTRK Fusions: Results From the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol EAY131-Z1E.

JCO precision oncology·2026

Crizotinib in Patients with Tumors with MET Amplification or Exon 14 Deletion: Results from the NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocols C1 and C2.

Clinical cancer research : an official journal of the American Association for Cancer Research·2026

Phase II Study of Dabrafenib and Trametinib in Patients With Tumors With BRAFV600E Mutations: Updated Results From NCI-MATCH ECOG-ACRIN Trial (EAY131) Subprotocol H.

JCO precision oncology·2026

See all related articles