Vandetanib to Overcome Endocrine Resistance in Estrogen Receptor Positive Breast Cancer

Introduction: ERK/MAPK activation is a common mechanism of resistance to endocrine therapy in estrogen receptor positive (ER+) breast cancer. We have shown that the tyrosine kinase inhibitor Vandetanib reduces ERK/MAPK activation through RET and EGFR in endocrine sensitive breast cancer. We investigate Vandetanib’s antitumor effects in ER+ endocrine resistant and translational models. Methods: We obtained the endocrine resistant cell lines MCF7-Tam, MCF7-Exe, and T47D-Tam and their parental sensitive lines MCF7 and T47D. Cell growth with Vandetanib 10 µM or vehicle at 72 hours was measured by CellTiter-Glo. A novel ex vivo treatment model coupled with 10X genomics single cell RNA sequencing (scRNA-seq) was used to assess Vandetanib response in a primary ER+/HER2- tumor. Results: MCF7-Tam and T47D-Tam have increased RET expression relative to parental lines, and MCF7-Exe overexpresses EGFR (p < 0.01). Vandetanib reduced viability in MCF7-Tam by 52% (p < 0.01), in MCF7-Exe by 58% (p < 0.01), and in T47D-Tam by 36% (p = 0.02). Two ER+/HER2- patient derived organoids (PDO) were generated and validated by RNAseq and immunofluorescence. PDO2 has increased RET expression (3 times PDO1) and is significantly more sensitive to Vandetanib (p < 0.01). ScRNA-seq analysis for primary ER+/HER2- tumor cells treated with Vandetanib demonstrates down-regulated ERK/MAPK signatures including PDGFR-ERK (qvalue<0.01) and nRAS (q=0.01), and inflammatory signatures including TNFA/NFKB (q<0.01) compared with controls without Vandetanib treatment. Conclusion: Vandetanib has significant antiproliferative effects in ER+/HER2- endocrine resistant cells and a highly RET-expressing ER+ PDO, and targets highly resistant RET and EGFR. Future studies should focus on RET/EGFR-ERK/MAPK driven tumors and effects of Vandetanib on the immune microenvironment.