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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer
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Integration of Bioinformatics Approaches and Experimental Validations to Understand the Role of Notch Signaling in Ovarian Cancer

Published on: January 12, 2020

Targeting both Notch and ErbB-2 signalling pathways is required for prevention of ErbB-2-positive breast tumour

K Pandya1, K Meeke, A G Clementz

  • 1Molecular Biology Program, Loyola University Chicago, 2160 South First Avenue, Maywood, IL 60153, USA.

British Journal of Cancer
|August 18, 2011
PubMed
Abstract

Insights

Combining a Notch inhibitor with trastuzumab or lapatinib shows promise for treating ErbB-2-positive breast cancer, reducing recurrence and overcoming resistance. This dual-pathway inhibition could benefit patients with recurrent, trastuzumab-resistant disease.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cancer Research

Background:

  • Notch-1 activation by trastuzumab contributes to treatment resistance in breast cancer.
  • ErbB-2-positive breast tumors, including BT474 cells, are a focus of this study.
  • Trastuzumab resistance is a significant clinical challenge in ErbB-2-positive breast cancer.

Purpose of the Study:

  • To evaluate the preclinical efficacy of combining a Notch inhibitor (GSI) with trastuzumab in sensitive and resistant ErbB-2-positive breast tumors.
  • To assess the potential of combining lapatinib with a GSI for inducing tumor regression in ErbB-2-positive breast cancer.

Main Methods:

  • Generation of orthotopic breast tumor xenografts using trastuzumab-sensitive and -resistant BT474 cells.
  • In vivo investigation of two gamma-secretase inhibitors (GSIs): LY 411 575 and MRK-003.
  • Evaluation of antitumour activities of combination therapies involving GSIs, trastuzumab, and lapatinib.

Main Results:

  • Combination of trastuzumab with MRK-003 GSI completely prevented tumor recurrence in sensitive tumors.
  • Trastuzumab plus LY 411 575 GSI significantly reduced tumor recurrence.
  • Lapatinib plus MRK-003 GSI demonstrated a significant reduction in tumor growth.
  • GSIs partially reversed trastuzumab resistance in resistant breast tumors.

Conclusions:

  • Combined inhibition of Notch and ErbB-2 signaling pathways may decrease recurrence rates in ErbB-2-positive breast tumors.
  • This combination therapy holds potential for treating recurrent trastuzumab-resistant breast cancer.
  • Targeting both Notch and ErbB-2 pathways offers a promising strategy for overcoming treatment resistance.

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