Fibroblast–tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways
Abstract
Factors stemming from the tumor microenvironment can modulate drug resistance. Therefore, rational approaches to design efficacious targeted therapies are needed. Here, we show that fibroblasts reduce lapatinib sensitivity in a subset of HER2 + breast cancer cells via paracrine signaling that can be reversed by targeting downstream survival programs such as MTOR and antiapoptotic proteins (BCL-XL and MCL-1). Our finding that fibroblasts derived from either primary tumor or metastatic sites limit lapatinib response has important implications for developing treatment strategies that can restore sensitivity in multiple drug-resistant microenvironments. Due to the diversity of microenvironmental factors between these sites, targeting downstream survival programs instead of individual factors released by fibroblasts represents a promising strategy to combat microenvironment complexity.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Jun 29, 2020
- Source ID
- 10.1073/pnas.2000648117
Entities
People
- Alexis L Scott
- Deborah A. Dillon
- Gordon B. Mills
- Ioannis K Zervantonakis
- Jia-Ren Lin
- Joan Brugge
- Laura M Selfors
- Matthew D Poskus
- Peter K. Sorger
- Shailja Pathania
Organizations
- Brigham and Women's Hospital
- Harvard Medical School
- National Cancer Institute
- Oregon Health & Science University
- Susan G. Komen for the Cure
- The Breast Cancer Research Foundation
- United States Department of Defense
- University of Massachusetts Boston
- University of Pittsburgh
- University of Pittsburgh Cancer Institute