Abemaciclib is effective against pancreatic cancer cells and synergizes with HuR and YAP1 inhibition
Authors: Teena Dhir, Christopher W. Schultz, Aditi Jain, Samantha Z Brown, Alex Haber, Austin Goetz, Chunhua Xi, Gloria H. Su, Liang Xu, James Posey, Wei Jiang, Charles J. Yeo, Talia Golan, Michael J. Pishvaian, Jonathan R. Brody
Summary:
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 (Lilly, IN) has nanomolar IC50's in PDAC cell lines and decreases growth through inhibition of phospho-Rb (pRb), G1 cell cycle arrest, apoptosis, and the senescent phenotype detected with β-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 to no treatment (p<0.0001) accompanying a decrease in both pRb and Ki67. We determined that inhibitors of HuR (ELAVL1), a pro-survival mRNA stability factor that regulates cyclin D1; and an inhibitor of Yes-Associated Protein 1 (YAP1), a pro-oncogenic, transcriptional co-activator 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. Additionally, 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 co-resistance to gemcitabine and 5-FU, but not to HuR or YAP1 inhibitors as compared to no treatment controls. We believe that our data provide compelling pre-clinical evidence for an abemaciclib-combination-based clinical trial in patients with PDAC. Implications: Our data suggests that abemaciclib may be therapeutically relevant for the treatment in PDAC, specially as part of a combination regimen inhibiting YAP1 or HuR.
Source: Molecular Cancer Research, 2019; molcanres.0589.2019
Summary:
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 (Lilly, IN) has nanomolar IC50's in PDAC cell lines and decreases growth through inhibition of phospho-Rb (pRb), G1 cell cycle arrest, apoptosis, and the senescent phenotype detected with β-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 to no treatment (p<0.0001) accompanying a decrease in both pRb and Ki67. We determined that inhibitors of HuR (ELAVL1), a pro-survival mRNA stability factor that regulates cyclin D1; and an inhibitor of Yes-Associated Protein 1 (YAP1), a pro-oncogenic, transcriptional co-activator 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. Additionally, 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 co-resistance to gemcitabine and 5-FU, but not to HuR or YAP1 inhibitors as compared to no treatment controls. We believe that our data provide compelling pre-clinical evidence for an abemaciclib-combination-based clinical trial in patients with PDAC. Implications: Our data suggests that abemaciclib may be therapeutically relevant for the treatment in PDAC, specially as part of a combination regimen inhibiting YAP1 or HuR.
Source: Molecular Cancer Research, 2019; molcanres.0589.2019