Soluble TNFα blockade overcomes lapatinib resistance, inhibits cell and unleashes an innate immune response in HER2+ breast cancer

MAURO, F; MERCOGLIANO MF; ROLDAN DEAMICIS A; ELIZALDE PV; BRUNI S; DE MARTINO M; SCHILLACI R

Congreso; Reunión Anual de SAIC; 2020

Lapatinib (L) is a dual EGFR/HER2 tyrosine kinase inhibitor used in HER2+ metastatic breast cancer (BC), but its clinical benefit is less than 30%. We showed that soluble TNFα (sTNFα) induces trastuzumab (T) resistance by upregulating mucin 4 (MUC4), a transmembrane glycoprotein that shields the T epitope on the HER2 molecule, and that women with HER2+/MUC4+ BC have worse survival. Here we studied the role of sTNFα blockade in cell migration, tumor growth, and in the innate immune response in JIMT-1, a T and L-resistant HER2+ BC model. To block sTNFα we used INB03, a TNFα dominant-negative protein (DN). JIMT-1 cell migration was not prevented by L or DN treatment alone, but the combination of L+DN inhibited migration by 50% (p