Science and Technology Production
Congress
Authorship
Bruni S
;
Mauro F
;
Naveiro, S
;
Cordo Russo R
;
Dupont A
;
Mercogliano, María F.
;
SCHILLACI, ROXANA
Date
2026
Publishing House and Editing Place
AACR
Summary
Information provided by the agent in
SIGEVA
Background Trastuzumab deruxtecan (T-DXd) is the second line of treatment in metastatic HER2-positive breast cancer. DESTINY-Breast03 demonstrated that the overall survival in this setting was 52.6 %. Therefore, biomarkers of therapy efficacy and novel agents to improve T-DXd outcome are needed. We have demonstrated that mucin 4 (MUC4) is an independent biomarker of poor disease-free survival in HER2-positive breast cancer patients treated with trastuzumab. In addition, we have shown that TNF i...
Background Trastuzumab deruxtecan (T-DXd) is the second line of treatment in metastatic HER2-positive breast cancer. DESTINY-Breast03 demonstrated that the overall survival in this setting was 52.6 %. Therefore, biomarkers of therapy efficacy and novel agents to improve T-DXd outcome are needed. We have demonstrated that mucin 4 (MUC4) is an independent biomarker of poor disease-free survival in HER2-positive breast cancer patients treated with trastuzumab. In addition, we have shown that TNF induces MUC4 expression and that soluble TNF (sTNF) neutralization by INB03 (DN) overcomes trastuzumab resistance in preclinical models. Previously, we observed that administration of 1.25 mg/kg, 2.5 mg/kg or 5 mg/kg T-DXd in nude mice reduces JIMT-1 tumor growth by 37%, 61% and 83%, respectively. Administration of 1.25mg/kg T-DXd + DN induces a tumor reduction mimicking 5 mg/kg dose. Now, we would like to explore whether TNF-induced MUC4 hampers T-DXd antitumor effect. MethodsThe HER2-positive trastuzumab-resistant JIMT-1 cells were engineered to express a doxycycline (Dox)-inducible shRNA targeting human MUC4 rendering JIMT-shMUC4 cells. These cells were injected in nude mice. When JIMT-1-shMUC4 tumors were established, animals were divided into two groups which were administered or not with Dox, and treated with 2.5 mg/kg IgG, 2.5 mg/kg T-DXd (T-DXd 2.5), or 1.25 mg/kg T-DXd (T-DXd 1.25), DN 10 mg/kg or the combined therapies (n= 6-8/group). T-DXd and IgG were administered i.v. on days 0, 7 and 14. DN was administered i.p. twice a week for 3 weeks. Tumor growth was monitored and differences among groups were analysed by two-way ANOVA.ResultsIn JIMT-1shMUC4 tumors without Dox, tumor growth was inhibited with T-DXd 1.25 in a 58% (p<0.05) and addition of DN lowered it to 85% (p<0.0001) vs IgG being T-DXd 1.25 + DN reduction significant vs T-DXd 1.25 alone (p<0.05). T-DXd 2.5 decreased growth by 108% (P<0.001) and T-DXd 2.5 + DN by 108% (P<0.0001) vs IgG. When MUC4 was silenced in JIMT-1 shMUC4 tumors with Dox administration, T-DXd 1.25 induced a reduction of tumor growth (87%, p<0.05) and addition of DN did not further increase the effect of T-DXd (87%, p<0.01). T-DXd 2.5 decreased growth by 105% (P<0.05) and T-DXd 2.5 + DN by 129% (P<0.01) vs IgG.ConclusionOur results suggest that MUC4 impairs T-DXd antitumor effect when it is administered at low dose (1.25mg/kg) and that TNF blockade can overcome this effect by downregulating MUC4 expression. MUC4 expression seems not to influence 2.5mg/kg T-DXd effect. As bioavailability of T-DXd can be affected by the tumor microenvironment characteristics, we propose that MUC4 would be a suitable biomarker to evaluate T-DXd resistance. In this case, addition of sTNF blockade would provide a rational therapeutic option.
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Key Words
IMMUNE RESPONSETNFT-DXdBREAST CANCER