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Genetic profiles associated with resistance to palbociclib

in combination with fulvestrant in hormone-receptor

positive breast cancer preclinical model

Yong Wha Moon,
Hematology and Oncology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University,

Seongnam, Korea.

ABSTRACT RESULTS

Background: Breast cancer represents the number one global cancer 1. Palbociclib-resistant genes by microarray
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 Drug resistant mouse

occurs in almost all cases. However, little is known about CDK4/6 inhibitor RNA
resistance. Microarra

Methods: Xenografting with HR-positive breast cancer cell line was y Palbociclib resistance
Control
performed in nude mice. When the tumor size reached 50-100 mm , drug v Fulvestrant + palbociclib resistance
3
Fulvestrant resistance
treatment was initiated. Palbociclib ± fulvestrant resulted in an initial dose- s Palbociclib-resistant genes
dependent decrease in xenograft tumor size and subsequently acquired v Gene Fold

resistance occurred (>25% regrowth from maximal reduction) after 8-9 s v
s
months. Using xenograft tumors, RNA microarray and whole exome SNORA14B -3.090357

sequencing (WES) were performed to find out resistance mechanisms of TPT1 -2.33181

fulvestrant/palbociclib. v v SNORA74A -2.325456
s
Results: RNA microarray revealed SNORA14B (-3.09X), TPT1(-2.33X), s SYNPO2 2.122405
SNORA74A(-2.32X) , SYNPO2(2.12X), S100A7A(-2.10X), SNORD10(- S100A7A -2.100098

1.64X), KIR2DL2(-1.61X), PGM5(-1.55X) as palbociclib-resistance genes. SNORD10 -1.648976

In addition, WES revealed ACLY, PRB4, and SMPD1 genes as KIR2DL2 -1.610371
palbociclib/fulvestrant combination-resistance genes. We also found PGM5 -1.554079

fulvestrant resistance genes such as AGR3, ELOVL2, GFRA1, GREB1,
IGF1R, IGKV1-17, NRIP1, PPM1K, TM4SF1 by WES. Those resistance 2. Mutations from PALOMA-3 found in this study by WES

genes are under further validation.
ESR1
PIK3CA
TP53 Frame shift variant
EXPERIMENTAL SUMMARY NF1 Missense variant

ERBB2 Synonymous variant
AKT1 Missense + disruptive_inframe variant

RB1 Synonymous + missense variant
Control
KRAS
CDKN1B

MCF7 Cell line FGFR2
Fulvestrant CDK4
CDK6
FGFR3 Value
ACLY Control
Palbociclib
PRB4 Fulvestrant

SMPD1 Combination
Palbociclib
Nude mouse
Fulvestrant + Palbociclib 3. Mutations associated with palbociclib/fulvestrant combination resistance

Control Fulvestrant

COMB_ ONLY

12 2 11 ACLY

DDX60L
464
4 3 LRCH2

OTOA

8 PRB4

RNF10
SMPD1

Combination ZDHHC8

CONCLUSION

TEST category Test chip

We found out Palbociclib and/or fulvestrant -resistance genes in animal model. Our
WES Agilent SureSelect V6 200X
Palbociclib/fulvestrant - resistant animal model could be used for drug development to
overcome CDK4/6 inhibitor resistance.
Microarray Affymetrix Human Gene 2.0 ST Array

Copyright © 2022 Yong Wha Moon (ymoon@cha.ac.kr )