title: CDK4/6 inhibitors have potent activity in combination with pathway selective therapeutic agents in models of pancreatic cancer.
abstract: Pancreatic ductal adenocarcinoma (PDA) has a poor prognosis, in part, due to the therapy-recalcitrant nature of the disease. Loss of the CDK4/6 inhibitor CDKN2A is a signature genetic event in PDA. Therefore, PDA may be amenable to treatment with pharmaceutical CDK4/6 inhibitors. Surprisingly, response to CDK4/6 inhibition was highly variable in PDA models, and associated with differential suppression of gene expression. Mitotic genes were repressed and FOXM1 was uniformly attenuated; however, genes involved in DNA replication were uniquely suppressed in sensitive models. Aberrant induction of Cyclin E1 was associated with resistance, and knockdown demonstrated synergistic suppression of the cell cycle with CDK4/6 inhibition. Combination therapies are likely required for the effective treatment of disease, and drug screening demonstrated additive/antagonistic interactions with CDK4/6 inhibitors. Agents dependent on mitotic progression (taxanes/PLK1 inhibitors) were antagonized by CDK4/6 inhibition, while the response to 5-FU and gemcitabine exhibited drug specific interactions. PI3K/MTOR and MEK inhibitors potently cooperated with CDK4/6 inhibition. These agents were synergistic with CDK4/6 inhibition, blocked the aberrant upregulation of Cyclin E1, and yielded potent inhibition of tumor cell growth. Together, these data identify novel mechanisms of resistance to CDK4/6 inhibitions and provide a roadmap for combination therapies in the treatment of PDA.
authors.affiliation: Department of Pathology , UT Southwestern, Dallas TX.
authors.forename: Jorge
authors.initials: J
authors.lastname: Franco
authors.affiliation: Department of Pathology , UT Southwestern, Dallas TX; Simmons Cancer Center, UT Southwestern, Dallas TX.
authors.forename: Agnieszka K
authors.initials: AK
authors.lastname: Witkiewicz
authors.affiliation: Department of Pathology , UT Southwestern, Dallas TX; Simmons Cancer Center, UT Southwestern, Dallas TX.
authors.forename: Erik S
authors.initials: ES
authors.lastname: Knudsen
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D045744:Cell Line, Tumor; D051358:Cyclin-Dependent Kinase 4 / Q000037:antagonists & inhibitors*; D051361:Cyclin-Dependent Kinase 6 / Q000037:antagonists & inhibitors*; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000172:deficiency; D015870:Gene Expression; D020869:Gene Expression Profiling / Q000379:methods; D006801:Humans; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000235:genetics; D010879:Piperazines / Q000494:pharmacology; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology; D014162:Transfection
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; C495900:CDK4 protein, human; C495911:CDK6 protein, human; D051358:Cyclin-Dependent Kinase 4; D051361:Cyclin-Dependent Kinase 6; C500026:palbociclib