Soluble TNFA blockade enhances trastuzumab deruxtecan antitumor effect in HER2-positive breast cancer model

BRUNI S; MAURO F; PROIETTI C ; CORDO-RUSSO R; MERCOGLIANO MF; SCHILLACI R

San Antonio

Congreso; San Antonio Breast Cancer Conference; 2023

Background. Based on data from DESTINY-Breast03 and DESTINY-Breast04 trials, patients with metastatic high or low HER2+ breast cancer subtype will receive trastuzumab deruxtecan (TDXd), however, at 24 months of treatment 50% of the patients present progressive disease. We have shown that mucin 4 (MUC4) expression is an independent predictor of poor response to trastuzumab in HER2+ breast cancer patients. MUC4 is upregulated by soluble TNFα (sTNFα) produced by the tumor. MUC4 expression confers primary trastuzumab resistance by hindering trastuzumab epitope on the HER2 molecule preventing its binding and downstream antitumor effects. In addition, MUC4 expression poses an immunosuppressive TME. In a murine model, downregulating MUC4 with INB03, a dominant negative drug that selectively impairs sTNF activity/function, converts the immunosuppressive, tumor permissive TME to an inflammatory, antitumor TME. Our goal is to study whether sTNFα blockade can improve TDXd effect in a HER2-targeted therapies resistant model.Methods JIMT-1 HER2+ overexpressing breast cancer model resistant to trastuzumab, pertuzumab and lapatinib that expresses MUC4. JIMT-1 tumors growing in nude mice were treated with (1) IgG 5 mg/kg, (2) TDXd 5 mg/kg, (3) TDXd 2.5 mg/kg, (4) TDXd 1.25 mg/kg, (5) INB03 10 mg/kg, (6) TDXd 5 mg/kg +INB03, (7) TDXd 2.5 mg/kg +INB03 and (8) TDXd 1.25 mg/kg +INB03. TDXd and IgG i.v. on days 0, 7 and 14. INB03 i.p. twice a week for 21 days. Tumor growth was determined by its volume twice a week.Results The dose-response curve of TDXd exhibited an inhibition in tumor growth of 83%, 61% and 37 % for the 5 mg/kg, 2.5 mg/kg and 1.25 mg/kg doses, respectively. INB03 alone had no antitumor effect. Combination of TDXd with INB03 resulted in an increase of the antitumor effect of TDXd as the inhibitory effect was 98% for TDXd 5 mg/kg +INB03, 81 % for TDXd 2.5 mg/kg +INB03 and 73% for TDXd 1.25 mg/kg +INB03. Conclusions Our results suggest that sTNFα blockade is able to enhance TDXd effect in a HER2-targeted therapies resistant model. Notably the administration of TDXd 1.25 mg/kg+ INB03 achieved similar antitumor effect than TDXd 5 mg/kg. This finding highlights that neutralization of sTNFα is an important player to be tackled to increase sensitiveness to the TDXd effect and may convert short term responders to long-term responders.