CDK4/6 dual inhibitor abemaciclib demonstrates compelling preclinical activity against esophageal adenocarcinoma: a novel therapeutic option for a deadly disease

Abstract

Esophageal adenocarcinoma (EAC) is a deadly disease with limited therapeutic options. In the present study, we determined the preclinical efficacy of CDK4/6 inhibitor abemaciclib for treatment of EAC. In vitro, apoptosis, proliferation, and pathway regulation were evaluated in OE19, OE33, and FLO1 EAC cell lines. In vivo, esophagojejunostomy was performed on rats to induce EAC. At 36 weeks post-surgery, MRI and endoscopic biopsy established baseline tumor volume and molecular correlates, respectively. Next, the study animals were randomized to 26mg/kg intraperitoneal abemaciclib treatment or vehicle control for 28 days. Pre and post treatment MRIs, histopathology, and qRT-PCR were utilized to determine response. Our results demonstrated treatment with abemaciclib lead to increased apoptosis, and decreased proliferation in OE19 (p=0.185), OE33 (p=0.048), and FLO1 (p=0.043) with anticipated downstream molecular inhibition. In vivo, 78.9% of treatment animals demonstrated >20% tumor volume decrease (placebo 0%). Mean tumor volume changed in the treatment arm by -65.5% (placebo +133.5%) (p<0.01), and prevalence changed by -37.5% (placebo +16.7%) (p<0.01). Pre vs post treatment qRT-PCR demonstrated significant inhibition of all downstream molecular correlates. Overall our findings suggest potent antitumor efficacy of abemaciclib against EAC with evident molecular pathway inhibition and reasonable safety, establishing the rationale for future clinical development.

Abemaciclib, A Selective CDK4/6 Inhibitor, Restricts the Growth of Pediatric Ependymomas

“…In this study, we demonstrated that abemaciclib treatment resulted in decreased expression of genes related to the cell cycle and DNA repair through inhibiting RB phosphorylation and total RB protein levels. That abemaciclib not only inhibits RB phosphorylation but also total RB levels was also observed in previous studies [34,35]. Phosphorylation of the RB protein causes dissociation of the E2F protein, which then translocates to the nucleus to regulate target gene expression [36].…”

Genomic Analysis of Response to Neoadjuvant Chemotherapy in Esophageal Adenocarcinoma

“…CDK4/6 inhibitors could be promising therapeutics for non-responders to NAC with copy number changes in this axis. In particular, CDK4/6 inhibitors palbociclib, ribociclib and abemaciclib have shown efficacy in in vitro models of EAC [ 25 , 67 ] and promising results in breast cancer, non-small cell lung cancer and melanoma patients [ 68 ]. Similarly, the use of ABT-348, a multitarget Aurora kinase and VEGFR inhibitor [ 69 ], is currently being explored in phase I and II clinical trials in patients with CDKN2A -deficient tumors [ 70 , 71 ], suggesting additional targeted therapies to this axis are closer to clinical adoption.…”

Genomic analysis of response to neoadjuvant chemotherapy in esophageal adenocarcinoma

“…CDK4/6 inhibitors could be promising therapeutics for non-responders to NAC with copy number changes in this axis. In particular, CDK4/6 inhibitors palbociclib, ribociclib (Frankell et al 2019) and abemaciclib have shown efficacy in in vitro models of EAC (Frankell et al 2019; Kosovec et al 2017) and promising results in breast cancer, non-small cell lung cancer and melanoma patients (Patnaik et al 2016). Similarly, the use of ABT-348, a multitarget Aurora kinase and VEGFR inhibitor (Maitland et al 2018), is currently being explored in phase I and II clinical trials in patients with CDKN2A -deficient tumors (Sharma 2015; Hong 2015), suggesting additional targeted therapies to this axis are closer to clinical adoption.…”