Dual Inhibition of the TrkA and JAK2 Pathways Using Entrectinib and Pacritinib Suppresses the Growth and Metastasis of HER2-Positive and Triple-Negative Breast Cancers

Authors

Angelina T Regua
Shivani Bindal
Mariana K Najjar
Chuling Zhuang
Munazza Khan
Austin B J Arrigo
Anneliese O Gonzalez
Xinhai R Zhang
Jay-Jiguang Zhu
Kounosuke Watabe
Hui-Wen Lo

Publication Date

8-10-2024

Journal

Cancer Letters

Abstract

HER2-positive and triple-negative breast cancers (TNBC) are difficult to treat and associated with poor prognosis. Despite showing initial response, HER2-positive breast cancers often acquire resistance to HER2-targeted therapies, and TNBC lack effective therapies. To overcome these clinical challenges, we evaluated the therapeutic utility of co-targeting TrkA and JAK2/STAT3 pathways in these breast cancer subtypes. Here, we report the novel combination of FDA-approved TrkA inhibitors (Entrectinib or Larotrectinib) and JAK2 inhibitors (Pacritinib or Ruxolitinib) synergistically inhibited in vitro growth of HER2-positive breast cancer cells and TNBC cells. The Entrectinib-Pacritinib combination inhibited the breast cancer stem cell subpopulation, reduced expression of stemness genes, SOX2 and MYC, and induced apoptosis. The Entrectinib-Pacritinib combination suppressed orthotopic growth of HER2-positive Trastuzumab-refractory breast cancer xenografts and basal patient-derived xenograft (PDXs), reduced tumoral SOX2 and MYC, and induced apoptosis in both mouse models. The Entrectinib-Pacritinib combination inhibited overall metastatic burden, and brain and bone metastases of intracardially inoculated TNBC cells without toxicity. Together, our results demonstrate for the first time that co-inhibition of TrkA and JAK2 synergistically suppresses breast cancer growth and metastasis, thereby providing preclinical evidence that supports future clinical evaluations.

Keywords

Humans, Janus Kinase 2, Triple Negative Breast Neoplasms, Benzamides, Animals, Female, Pyrimidines, Receptor, ErbB-2, Cell Line, Tumor, Receptor, trkA, Mice, Xenograft Model Antitumor Assays, Cell Proliferation, Indazoles, Pyrazoles, Signal Transduction, Antineoplastic Combined Chemotherapy Protocols, Apoptosis, Protein Kinase Inhibitors, Mice, Nude, Drug Synergism, Bridged-Ring Compounds, Breast cancer, TrkA, JAK2, Breast cancer metastasis, Combined targeted therapy

DOI

10.1016/j.canlet.2024.217023

PMID

38852701

PMCID

PMC11533721

PubMedCentral® Posted Date

11-4-2024

PubMedCentral® Full Text Version

Author MSS

Published Open-Access

yes