RT Journal Article
SR Electronic
T1 Targeting cancer stem cells with a pan-BCL-2 inhibitor in preclinical and clinical settings in patients with gastroesophageal carcinoma
JF Gut
JO Gut
FD BMJ Publishing Group Ltd and British Society of Gastroenterology
SP gutjnl-2020-321175
DO 10.1136/gutjnl-2020-321175
A1 Shumei Song
A1 Qiongrong Chen
A1 Yuan Li
A1 Guang Lei
A1 Ailing Scott
A1 Longfei Huo
A1 Cordelia Y Li
A1 Jeannelyn Santiano Estrella
A1 Arlene Correa
A1 Melissa Pool Pizzi
A1 Lang Ma
A1 Jiankang Jin
A1 Bin Liu
A1 Ying Wang
A1 Lianchun Xiao
A1 Wayne L Hofstetter
A1 Jeffrey H Lee
A1 Brian Weston
A1 Manoop Bhutani
A1 Namita Shanbhag
A1 Randy L Johnson
A1 Boyi Gan
A1 Shaozhong Wei
A1 Jaffer A Ajani
YR 2021
UL http://gut.bmj.com/content/early/2021/01/23/gutjnl-2020-321175.abstract
AB Objective Gastro-oesophageal cancers (GEC) are resistant to therapy and lead to poor prognosis. The cancer stem cells (CSCs) and antiapoptotic pathways often confer therapy resistance. We sought to elucidate the antitumour action of a BCL-2 inhibitor, AT101 in GEC in vitro, in vivo and in a clinical trial.Methods Extensive preclinical studies in vitro and in vivo were carried out to establish the mechanism action of AT101 on targeting CSCs and antiapoptotic proteins. A pilot clinical trial in patients with GEC was completed with AT-101 added to standard chemoradiation.Results Overexpression of BCL-2 and MCL-1 was noted in gastric cancer tissues (GC). AT-101 induced apoptosis, reduced proliferation and tumour sphere formation in MCL-1/BCL-2 high GC cells. Interestingly, AT101 dramatically downregulated genes (YAP-1/Sox9) that control CSCs in GEC cell lines regardless of BCL-2/MCL-1 expression. Addition of docetaxel to AT-101 amplified its antiproliferation and induced apoptosis effects. In vivo studies confirmed the combination of AT101 and docetaxel demonstrated stronger antitumour activity accompanied with significant decrease of CSCs biomarkers (YAP1/SOX9). In a pilot clinical trial, 13 patients with oesophageal cancer (EC) received AT101 orally concurrently with chemoradiation. We observed dramatic clinical complete responses and encouraging overall survival in these patients. Clinical specimen analyses revealed that AT-101 dramatically reduced the expression of CSCs genes in treated EC specimens indicating antitumour activity of AT101 relies more on its anti-CSCs activity.Conclusions Our preclinical and clinical data suggest that AT-101 overcomes resistance by targeting CSCs pathways suggesting a novel mechanism of action of AT101 in patients with GEC.