Page 10 - ebook

[D. Medicine/Translational Research] D-5

Genetic profiles associated with resistance to palbociclib in

combination with fulvestrant in hormone-receptor positive

breast cancer preclinical model

Yong Wha Moon¹*, Jun Hee Sung², Kamal Pandey¹,

¹Hematology & Oncology, CHA Bundang Medical Center, Seongnam 13496, Korea, ²School of Medicine, CHA

University, Seongnam 13488, Korea

Background: Breast cancer represents the number one global cancer burden in women. Although cyclin-dependent

kinase 4 and 6 (CDK4/6) inhibitors are a highly effective therapy for hormone receptor (HR)-positive breast cancer,
acquired resistance ultimately occurs in almost all cases. However, little is known about CDK4/6 inhibitor resistance.

Methods: Xenografting with HR-positive breast cancer cell line was performed in nude mice. When the tumor size
reached 50-100 mm3, drug treatment was initiated. Palbociclib ± fulvestrant 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. Using xenograft tumors, RNA microarray and whole exome sequencing (WES) were

performed to find out resistance mechanisms of fulvestrant/palbociclib. Results: 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. Conclusion: We found out Palbociclib and/or fulvestrant -resistance genes in animal model. Our
Palbociclib/fulvestrant - resistant animal model could be used for drug development to overcome CDK4/6 inhibitor

resistance.