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Fibroblast-tumor cell signaling limits HER2 kinase therapy response via activation of MTOR and antiapoptotic pathways
Ioannis K Zervantonakis1,2,3, Matthew D Poskus4, Alexis L Scott4
1Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15213; ioz1@pitt.edu joan_brugge@hms.harvard.edu.
Abstract:
Despite the implementation of multiple HER2-targeted therapies, patients with advanced HER2+ breast cancer ultimately develop drug resistance. Stromal fibroblasts represent an abundant cell type in the tumor microenvironment and have been linked to poor outcomes and drug resistance. Here, we show that fibroblasts counteract the cytotoxic effects of HER2 kinase-targeted therapy in a subset of HER2+ breast cancer cell lines and allow cancer cells to proliferate in the presence of the HER2 kinase inhibitor lapatinib. Fibroblasts from primary breast tumors, normal breast tissue, and lung tissue have similar protective effects on tumor cells via paracrine factors. This fibroblast-mediated reduction in drug sensitivity involves increased expression of antiapoptotic proteins and sustained activation of the PI3K/AKT/MTOR pathway, despite inhibition of the HER2 and the RAS-ERK pathways in tumor cells. HER2 therapy sensitivity is restored in the fibroblast cocultures by combination treatment with inhibitors of MTOR or the antiapoptotic proteins BCL-XL and MCL-1. Expression of activated AKT in tumor cells recapitulates the effects of fibroblasts resulting in sustained MTOR signaling and poor lapatinib response. Lapatinib sensitivity was not altered by fibroblasts in tumor cells that exhibited sustained MTOR signaling due to a strong gain-of-function PI3KCA mutation. These findings indicate that in addition to tumor cell-intrinsic mechanisms that cause constitutive PI3K/AKT/MTOR pathway activation, secreted factors from fibroblasts can maintain this pathway in the context of HER2 inhibition. Our integrated proteomic-phenotypic approach presents a strategy for the discovery of protective mechanisms in fibroblast-rich tumors and the design of rational combination therapies to restore drug sensitivity.
Insights
Stromal fibroblasts protect HER2-positive breast cancer cells from lapatinib therapy by activating the PI3K/AKT/MTOR pathway. Combination therapies targeting MTOR or BCL-XL/MCL-1 can restore drug sensitivity in these resistant tumors.
Area of Science:
- Oncology
- Cancer Biology
- Tumor Microenvironment
Background:
- Advanced HER2-positive breast cancer patients often develop resistance to HER2-targeted therapies.
- Stromal fibroblasts, prevalent in the tumor microenvironment, are associated with poor prognosis and drug resistance.
- Understanding fibroblast-mediated resistance mechanisms is crucial for improving treatment outcomes.
Purpose of the Study:
- To investigate how stromal fibroblasts influence the efficacy of HER2-targeted therapy in HER2-positive breast cancer.
- To elucidate the molecular mechanisms by which fibroblasts confer resistance to HER2 kinase inhibitors.
- To identify potential combination strategies to overcome fibroblast-mediated drug resistance.
Main Methods:
- Co-culture of HER2-positive breast cancer cell lines with fibroblasts from various tissue sources.
- Treatment with the HER2 kinase inhibitor lapatinib.
- Analysis of signaling pathways (PI3K/AKT/MTOR, RAS-ERK), apoptotic protein expression, and proteomic-phenotypic profiling.
- Evaluation of combination therapies targeting MTOR or antiapoptotic proteins (BCL-XL, MCL-1).
Main Results:
- Fibroblasts protected a subset of HER2-positive breast cancer cells from lapatinib-induced cytotoxicity, promoting proliferation.
- Fibroblast-mediated protection involved sustained activation of the PI3K/AKT/MTOR pathway and increased antiapoptotic protein expression.
- Combination therapy with MTOR or BCL-XL/MCL-1 inhibitors restored lapatinib sensitivity in co-cultured cells.
- Fibroblast effects were recapitulated by activated AKT in tumor cells and were independent of PI3KCA mutations.
Conclusions:
- Stromal fibroblasts secrete factors that maintain PI3K/AKT/MTOR pathway activation, contributing to HER2-targeted therapy resistance.
- Targeting the PI3K/AKT/MTOR pathway or key antiapoptotic proteins offers a rational approach to overcome fibroblast-mediated resistance.
- This study highlights the importance of the tumor microenvironment in drug resistance and suggests combination therapies for improved treatment.
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