TY - JOUR
T1 - Abemaciclib is effective against pancreatic cancer cells and synergizes with HuR and YAP1 inhibition
AU - Dhir, Teena
AU - Schultz, Christopher W.
AU - Jain, Aditi
AU - Brown, Samantha Z.
AU - Haber, Alex
AU - Goetz, Austin
AU - Xi, Chunhua
AU - Su, Gloria H.
AU - Xu, Liang
AU - Posey, James
AU - Jiang, Wei
AU - Yeo, Charles J.
AU - Golan, Talia
AU - Pishvaian, Michael J.
AU - Brody, Jonathan R.
N1 - Funding Information:
This study was performed with grant support from the Newell Devalpine Foundation, 1R01CA212600-01 (to J.R. Brody) and T32 training grant NIH/ NIGMS T32GM008562 (to T. Dhir). This work was also supported, in part, by a National Cancer Institute of the National Institutes of Health under a Cancer Center Support Grant 5P30CA056036-17 (SKCC, TJU). This study was not funded by Eli Lilly and Company. IHC slides were processed and stained by Raymond O'Neill, Medical Technologist at Thomas Jefferson University Hospital (Philadelphia, PA).
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/10/1
Y1 - 2019/10/1
N2 - Mutation or promoter hypermethylation of CDKN2A is found in over 90% of pancreatic ductal adenocarcinomas (PDAC) and leads to loss of function of cell-cycle inhibitors p16 (INK4A) and p14 (ARF) resulting in unchecked proliferation. The CDK4/6 inhibitor, abemaciclib, has nanomolar IC50s in PDAC cell lines and decreases growth through inhibition of phospho-Rb (pRb), G1 cell-cycle arrest, apoptosis, and the senescent phenotype detected with b-galactosidase staining and relevant mRNA elevations. Daily abemaciclib treatments in mouse PDAC xenograft studies were safe and demonstrated a 3.2-fold decrease in tumor volume compared with no treatment (P < 0.0001) accompanying a decrease in both pRb and Ki67. We determined that inhibitors of HuR (ELAVL1), a prosurvival mRNA stability factor that regulates cyclin D1, and an inhibitor of Yes-Associated Protein 1 (YAP1), a pro-oncogenic, transcriptional coactivator important for CDK6 and cyclin D1, were both synergistic with abemaciclib. Accordingly, siRNA oligonucleotides targeted against HuR, YAP1, and their common target cyclin D1, validated the synergy studies. In addition, we have seen increased sensitivity to abemaciclib in a PDAC cell line that harbors a loss of the ELAVL1 gene via CRISP-Cas9 technology. As an in vitro model for resistance, we investigated the effects of long-term abemaciclib exposure. PDAC cells chronically cultured with abemaciclib displayed a reduction in cellular growth rates (GR) and coresistance to gemcitabine and 5-fluorouracil (5-FU), but not to HuR or YAP1 inhibitors as compared with no treatment controls. We believe that our data provide compelling preclinical evidence for an abemaciclib combination-based clinical trial in patients with PDAC.
AB - Mutation or promoter hypermethylation of CDKN2A is found in over 90% of pancreatic ductal adenocarcinomas (PDAC) and leads to loss of function of cell-cycle inhibitors p16 (INK4A) and p14 (ARF) resulting in unchecked proliferation. The CDK4/6 inhibitor, abemaciclib, has nanomolar IC50s in PDAC cell lines and decreases growth through inhibition of phospho-Rb (pRb), G1 cell-cycle arrest, apoptosis, and the senescent phenotype detected with b-galactosidase staining and relevant mRNA elevations. Daily abemaciclib treatments in mouse PDAC xenograft studies were safe and demonstrated a 3.2-fold decrease in tumor volume compared with no treatment (P < 0.0001) accompanying a decrease in both pRb and Ki67. We determined that inhibitors of HuR (ELAVL1), a prosurvival mRNA stability factor that regulates cyclin D1, and an inhibitor of Yes-Associated Protein 1 (YAP1), a pro-oncogenic, transcriptional coactivator important for CDK6 and cyclin D1, were both synergistic with abemaciclib. Accordingly, siRNA oligonucleotides targeted against HuR, YAP1, and their common target cyclin D1, validated the synergy studies. In addition, we have seen increased sensitivity to abemaciclib in a PDAC cell line that harbors a loss of the ELAVL1 gene via CRISP-Cas9 technology. As an in vitro model for resistance, we investigated the effects of long-term abemaciclib exposure. PDAC cells chronically cultured with abemaciclib displayed a reduction in cellular growth rates (GR) and coresistance to gemcitabine and 5-fluorouracil (5-FU), but not to HuR or YAP1 inhibitors as compared with no treatment controls. We believe that our data provide compelling preclinical evidence for an abemaciclib combination-based clinical trial in patients with PDAC.
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U2 - 10.1158/1541-7786.MCR-19-0589
DO - 10.1158/1541-7786.MCR-19-0589
M3 - Article
C2 - 31383722
AN - SCOPUS:85072848997
SN - 1541-7786
VL - 17
SP - 2029
EP - 2041
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 10
ER -