Expression of MT4-MMP, EGFR and RB in triple negative breast cancer strongly sensitizes tumors to erlotinib and palbociclib combination therapy

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): epidermal growth factor receptor (EGFR), its recently identified partner (MT4-MMP) and retinoblastoma protein (RB). Experimental design: Immunohistochemistry (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 (E: erlotinib) or anti-CDK4/6 inhibitor (P: 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 (E or P) or combined (E+P) treatments. Results: EGFR and MT4-MMP were co-expressed 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 E and P treatments drastically reduced the in vitro proliferation of cells expressing EGFR and MT4-MMP when compared to control cells. Both TNBC xenografts and PDX expressing MT4-MMP, EGFR and RB but not PDX-TNBC with RB-loss were sensitive to E and P with an additive effect of combination therapy. Moreover, this combination was efficient in another PDX-TNBC expressing the three biomarkers and resistant to E alone. Conclusion. 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.

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