Inhibition of TFF3 synergizes with c-MET inhibitors to decrease the CSC-like phenotype and metastatic burden in...

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Estrogen receptor-positive (ER+) and HER2-positive (HER2+) mammary carcinoma (MC) presents treatment resistance due to HER2/ERα pathway interactions.
• Trefoil Factor-3 (TFF3) is implicated in mediating resistance to endocrine and HER2-targeted therapies in ER+ and ER+HER2+ MC.

Purpose of the Study:

• To elucidate the role and mechanism of TFF3 in ER+HER2+ MC.
• To identify novel combinatorial therapeutic strategies for ER+HER2+ MC.

Main Methods:

• Investigated TFF3 function using interfering RNA and small-molecule inhibitors (AMPC).
• Conducted high-throughput screening to identify synergistic drug combinations.
• Assessed effects on cell proliferation, survival, stem cell phenotype, invasion, and xenograft growth.
• Analyzed TFF3's mechanism involving c-MET signaling.

Main Results:

• Elevated TFF3 expression enhanced ER+HER2+ MC oncogenicity, including proliferation, survival, and stem cell characteristics.
• Targeting TFF3 with AMPC inhibited these oncogenic properties.
• AMPC synergized with c-MET inhibitors (c-METis) to reduce cell survival and stem cell phenotype.
• The combination therapy suppressed tumor growth and metastasis in vivo.

Conclusions:

• TFF3 antagonism is a viable therapeutic strategy for ER+HER2+ MC.
• Combining TFF3 inhibition with c-MET inhibition offers a promising approach for treating ER+HER2+ MC.
• TFF3 activates c-MET signaling in a positive-feedback loop, enhancing the cancer stem cell phenotype.