Abstract 17P
Background
Breast cancer is a leading cancer in global women cancer incidence. Although cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor combined with endocrine therapy is a highly effective therapy for hormone receptor (HR)-positive breast cancer, acquired resistance ultimately occurs in almost all cases. Preclinical in vivo model is essential to study mechanisms and to develop overcoming strategies of CDK4/6 inhibitor resistance.
Methods
We performed xenografting with HR-positive breast cancer cell line in nude mice. When the tumor size reached 50-100 mm3, palbociclib ± fulvestrant treatment was initiated. This resulted in an initial dose-dependent decrease in xenograft tumor size and subsequently acquired resistance occurred (>25% regrowth from maximal reduction) after 8-9 months. Mice were sacrificed and xenograft tumors were harvested. Using xenograft tumors, RNA microarray and whole exome sequencing (WES) were performed to find out resistance mechanisms of fulvestrant/palbociclib.
Results
We successfully established preclinical mouse model of palbociclib/fulvestrant resistance. RNA microarray revealed SNORA14B (-3.09X), TPT1(-2.33X), SNORA74A (-2.32X), SYNPO2 (2.12X), S100A7A (-2.10X), SNORD10(-1.64X), KIR2DL2 (-1.61X), PGM5 (-1.55X) as palbociclib-resistance genes. In addition, WES revealed ACLY, PRB4, and SMPD1 genes as palbociclib/fulvestrant combination-resistance genes. We also found fulvestrant resistance genes such as AGR3, ELOVL2, GFRA1, GREB1, IGF1R, IGKV1-17, NRIP1, PPM1K, TM4SF1 by WES. Those resistance genes are under further validation.
Conclusions
We established preclinical mouse model of palbociclib/fulvestrant resistance in HR-positive breast cancer. In addition we found out palbociclib/fulvestrant resistance-associated genes using this model. Our palbociclib/fulvestrant-resistance mouse model could be used for drug development to overcome CDK4/6 inhibitor and/or fulvestrant resistance.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Has not received any funding.
Disclosure
All authors have declared no conflicts of interest.