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Expression of MT4-MMP, EGFR, and RB in Triple-Negative Breast Cancer Strongly Sensitizes Tumors to Erlotinib and Palbociclib Combination Therapy
- Source :
- Clinical cancer research : an official journal of the American Association for Cancer Research. 25(6)
- Publication Year :
- 2018
-
Abstract
- Purpose: Here, we investigated the clinical relevance of an unprecedented combination of three biomarkers in triple-negative breast cancer (TNBC), both in human samples and in patient-derived xenografts of TNBC (PDX-TNBC): EGFR, its recently identified partner (MT4-MMP), and retinoblastoma protein (RB). Experimental Design: IHC analyses were conducted on human and PDX-TNBC samples to evaluate the production of the three biomarkers. The sensitivity of cancer cells expressing or not MT4-MMP to anti-EGFR (erlotinib) or anti-CDK4/6 inhibitor (palbociclib) was evaluated in vitro in 2D and 3D proliferation assays and in vivo using xenografts and PDX-TNBC displaying different RB, MT4-MMP, and EGFR status after single (erlotinib or palbociclib) or combined (erlotinib + palbociclib) treatments. Results: EGFR and MT4-MMP were coexpressed in >70% of TNBC samples and PDX-TNBC, among which approximately 60% maintained RB expression. Notably, approximately 50% of all TNBC and PDX-TNBC expressed the three biomarkers. Single erlotinib and palbociclib treatments drastically reduced the in vitro proliferation of cells expressing EGFR and MT4-MMP when compared with control cells. Both TNBC xenografts and PDX expressing MT4-MMP, EGFR, and RB, but not PDX-TNBC with RB loss, were sensitive to erlotinib and palbociclib with an additive effect of combination therapy. Moreover, this combination was efficient in another PDX-TNBC expressing the three biomarkers and resistant to erlotinib alone. Conclusions: We defined a new association of three biomarkers (MT4-MMP/EGFR/RB) expressed together in 50% of TNBC and demonstrated its usefulness to predict the TNBC response to anti-EGFR and anti-CDK4/6 drugs used in single or combined therapy.
- Subjects :
- 0301 basic medicine
Adult
endocrine system
Cancer Research
Combination therapy
Matrix Metalloproteinases, Membrane-Associated
Pyridines
Ubiquitin-Protein Ligases
Triple Negative Breast Neoplasms
Palbociclib
Piperazines
03 medical and health sciences
Erlotinib Hydrochloride
Mice
0302 clinical medicine
Breast cancer
In vivo
Cell Line, Tumor
Antineoplastic Combined Chemotherapy Protocols
Chlorocebus aethiops
medicine
Biomarkers, Tumor
Animals
Humans
Triple-negative breast cancer
Aged
Aged, 80 and over
business.industry
Middle Aged
medicine.disease
Prognosis
Immunohistochemistry
Xenograft Model Antitumor Assays
ErbB Receptors
Gene Expression Regulation, Neoplastic
Retinoblastoma Binding Proteins
030104 developmental biology
Oncology
Drug Resistance, Neoplasm
030220 oncology & carcinogenesis
Cancer cell
COS Cells
Cancer research
Feasibility Studies
Female
Erlotinib
business
medicine.drug
Subjects
Details
- ISSN :
- 15573265
- Volume :
- 25
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Accession number :
- edsair.doi.dedup.....c23c26b7d613c74478d6b2a881edc8da