Antitumor efficacy of CDK 4/6 dual inhibitor, abemaciclib, in an esophageal adenocarcinoma model.
Omstead, AN; Matsui, D; Kosovec, JE; Martin, SA; Kelly, RJ; Zaidi, AH; Jobe, BA
Published in: Journal of Clinical Oncology
e15598 Background: Esophageal adenocarcinoma (EAC) is a leading cause of cancer death, and current treatment options are extremely limited. Cell cycle regulators CDK6 and its homolog, CDK4, are known to be up-regulated in EAC and are associated with poor prognosis. At the molecular level, CDK4 and 6 bind to cyclin D1 and activates E2F transcription factor via phosphorylation of pRb. Up-regulation of this pathway leads to deregulation of the G1 checkpoint, resulting in increased cellular proliferation. Previously, studies have shown progressive up-regulation of CDK6 in pre-neoplastic lesions from Barrett’s esophagus to low-grade and high-grade dysplasia, thus establishing a rational for testing of a CDK4/6 dual inhibitor, Abemaciclib, in an established EAC model. Methods: Esophagojejunostomy was performed on Sprague-Dawley rats to induce gastroduodenojejunal reflux resulting in a sequence of histologic and molecular events that lead to the development esophageal adenocarcinoma. At 36 weeks post operatively, rats were randomized to receive Abemaciclib at 26 mg/kg or placebo (acetate buffer), intraperitoneally once daily for 4 weeks. Drug efficacy was evaluated with magnetic resonance imaging (MRI), endoscopic biopsy, histology, and CDK4/6 pathway expression by RT-PCR. Results: Twelve of 15 (80.0%) treated animals and all of 18 (100%) control animals reached study end-point. All of the treatment group mortality consisted of rats afflicted with moderate peritonitis, diarrhea and weight loss. Mean MRI tumor volume decreased by 93.55% in treatment animals and increased by 108.33% in control animals (P = 0.003). Treatment with Abemaciclib demonstrated tumor volume increase in 0% (control = 66.7%) (P = 0.0003), decrease in 75% (control = 0%) (P = 0.00001), and stable volume in 25% (control = 33.3%) (P = 0.63). EAC prevalence in treatment animals decreased by 50%; whereas, prevalence in control animals increased by 5.6% (P = 0.003). mRNA expression, pre- and post-treatment, demonstrated significant downregulation of CDK4, CDK6, RB1, pRB1 and Cyclin-D. Conclusions: Abemaciclib exhibits potent in vivo antitumor efficacy in a de novo EAC model, providing the rationale for clinical testing.
