Therapeutically targeting tumor microenvironment–mediated drug resistance in estrogen receptor–positive breast cancer

Author:

Shee Kevin1,Yang Wei1,Hinds John W.1,Hampsch Riley A.1,Varn Frederick S.12,Traphagen Nicole A.1,Patel Kishan1,Cheng Chao12ORCID,Jenkins Nicole P.3,Kettenbach Arminja N.3,Demidenko Eugene2,Owens Philip45,Faber Anthony C.6,Golub Todd R.7,Straussman Ravid8,Miller Todd W.19ORCID

Affiliation:

1. Department of Molecular and Systems Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH

2. Department of Biomedical Data Science, Geisel School of Medicine at Dartmouth, Lebanon, NH

3. Department of Biochemistry and Cell Biology, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH

4. Department of Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN

5. Research Medicine, Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN

6. VCU Philips Institute for Oral Health Research, School of Dentistry and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA

7. Broad Institute of MIT and Harvard, Cambridge, MA

8. Department of Molecular Cell Biology, Weizmann Institute of Science, Rehovot, Israel

9. Comprehensive Breast Program, Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, NH

Abstract

Drug resistance to approved systemic therapies in estrogen receptor–positive (ER+) breast cancer remains common. We hypothesized that factors present in the human tumor microenvironment (TME) drive drug resistance. Screening of a library of recombinant secreted microenvironmental proteins revealed fibroblast growth factor 2 (FGF2) as a potent mediator of resistance to anti-estrogens, mTORC1 inhibition, and phosphatidylinositol 3-kinase inhibition in ER+ breast cancer. Phosphoproteomic analyses identified ERK1/2 as a major output of FGF2 signaling via FGF receptors (FGFRs), with consequent up-regulation of Cyclin D1 and down-regulation of Bim as mediators of drug resistance. FGF2-driven drug resistance in anti-estrogen–sensitive and –resistant models, including patient-derived xenografts, was reverted by neutralizing FGF2 or FGFRs. A transcriptomic signature of FGF2 signaling in primary tumors predicted shorter recurrence-free survival independently of age, grade, stage, and FGFR amplification status. These findings delineate FGF2 signaling as a ligand-based drug resistance mechanism and highlights an underdeveloped aspect of precision oncology: characterizing and treating patients according to their TME constitution.

Funder

American Cancer Society

National Institutes of Health

Dartmouth College Norris Cotton Cancer Center

Publisher

Rockefeller University Press

Subject

Immunology,Immunology and Allergy

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