Abstract 1913: Soluble TNFα overcomes lapatinib resistance in HER2+ breast cancer

Lapatinib (LAP), a dual EGFR/HER2 tyrosine kinase inhibitor, is used as second-line therapy in women with HER2+ breast cancer (BC), but less than 25% of the patients achieve an objective response. An alternative therapeutic approach is needed to overcome LAP resistance in women with metastatic HER2+ BC, particularly in patients with central nervous system (CNS) metastasis where large biological molecules are not effective. Previously, we reported that women with HER2+ tumors that express transmembrane glycoprotein mucin 4 (MUC4) have worse survival, and that HER2+/MUC4+ cell lines resistant to trastuzumab (T) express higher levels of tumor necrosis factor α (TNF) than T-sensitive cell lines. In addition, we proved that inhibition of soluble TNF (sTNF) decreases the expression of MUC4 and reverses T resistance. The aim of this work is to evaluate the participation of sTNF and transmembrane TNF (tmTNF) in LAP resistance in vivo and in the anti-tumor innate immune response. We used the LAP-resistant human BC cell line JIMT-1 and compared etanercept (E), a fusion protein that non-selectively blocks both sTNF and tmTNF, with the dominant negative-TNF protein INB03 (DN), that neutralizes sTNF without affecting tmTNF. Nude mice bearing JIMT-1 tumors (~50 mm3), received LAP (100 mg/kg) daily by oral gavage and IgG (5 mg/kg), E (5 mg/kg), DN (10 mg/kg), LAP+E or LAP+DN, twice a week i.p. Tumor volume was monitored routinely. At the end of the experiment, tumor-infiltrating immune cells were evaluated by immunofluorescence and analyzed by flow cytometry. DN or E treatments did not exhibit any anti-tumor effect alone, but in combination with LAP (LAP+DN and LAP+E) tumor growth decreased in a 54% and 34% vs. IgG, respectively (p Citation Format: Sofia Bruni, Florencia L. Mauro, Mara De Martino, Agustina Roldan Deamicis, Maria F. Mercogliano, Roxana Schillaci, Patricia V. Elizalde. Soluble TNFα overcomes lapatinib resistance in HER2+ breast cancer [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1913.