YAP1-mediated CDK6 activation confers radiation resistance in esophageal cancer – Rationale for the combination of YAP1 and CDK4/6 inhibitors in esophageal cancer

Fan Li, Yan Xu, Bovey Liu, Pankaj Kumar Singh, Wei Zhao, Jiankang Jin, Guangchun Han, Ailing W. Scott, Xiaochuan Dong, Longfei Huo, Lang Ma, Melissa Pool Pizzi, Ying Wang, Yuan Li, Kazuto Harada, Min Xie, Heath Skinner, Sheng Ding, Linghua Wang, Sunil Krishnan & 3 others Randy L Johnson, Shumei Song, Jaffer A Ajani

Research output: Contribution to journalArticle

Abstract

Purpose: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo. Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/ YAP1 high esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1 þ and CD133 þ ), sensitized cells to irradiation, and showed a strong antitumor effect in vivo against radiation-resistant esophageal cancer cells. Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.

Original languageEnglish (US)
Pages (from-to)2264-2277
Number of pages14
JournalClinical Cancer Research
Volume25
Issue number7
DOIs
StatePublished - Apr 1 2019

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Esophageal Neoplasms
Radiation
Neoplastic Stem Cells
Therapeutics
Immunoblotting
Research Design
Immunohistochemistry
Phosphorylation
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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YAP1-mediated CDK6 activation confers radiation resistance in esophageal cancer – Rationale for the combination of YAP1 and CDK4/6 inhibitors in esophageal cancer. / Li, Fan; Xu, Yan; Liu, Bovey; Singh, Pankaj Kumar; Zhao, Wei; Jin, Jiankang; Han, Guangchun; Scott, Ailing W.; Dong, Xiaochuan; Huo, Longfei; Ma, Lang; Pizzi, Melissa Pool; Wang, Ying; Li, Yuan; Harada, Kazuto; Xie, Min; Skinner, Heath; Ding, Sheng; Wang, Linghua; Krishnan, Sunil; Johnson, Randy L; Song, Shumei; Ajani, Jaffer A.

In: Clinical Cancer Research, Vol. 25, No. 7, 01.04.2019, p. 2264-2277.

Research output: Contribution to journalArticle

Li, Fan ; Xu, Yan ; Liu, Bovey ; Singh, Pankaj Kumar ; Zhao, Wei ; Jin, Jiankang ; Han, Guangchun ; Scott, Ailing W. ; Dong, Xiaochuan ; Huo, Longfei ; Ma, Lang ; Pizzi, Melissa Pool ; Wang, Ying ; Li, Yuan ; Harada, Kazuto ; Xie, Min ; Skinner, Heath ; Ding, Sheng ; Wang, Linghua ; Krishnan, Sunil ; Johnson, Randy L ; Song, Shumei ; Ajani, Jaffer A. / YAP1-mediated CDK6 activation confers radiation resistance in esophageal cancer – Rationale for the combination of YAP1 and CDK4/6 inhibitors in esophageal cancer. In: Clinical Cancer Research. 2019 ; Vol. 25, No. 7. pp. 2264-2277.
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abstract = "Purpose: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo. Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/ YAP1 high esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1 {\th} and CD133 {\th} ), sensitized cells to irradiation, and showed a strong antitumor effect in vivo against radiation-resistant esophageal cancer cells. Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.",
author = "Fan Li and Yan Xu and Bovey Liu and Singh, {Pankaj Kumar} and Wei Zhao and Jiankang Jin and Guangchun Han and Scott, {Ailing W.} and Xiaochuan Dong and Longfei Huo and Lang Ma and Pizzi, {Melissa Pool} and Ying Wang and Yuan Li and Kazuto Harada and Min Xie and Heath Skinner and Sheng Ding and Linghua Wang and Sunil Krishnan and Johnson, {Randy L} and Shumei Song and Ajani, {Jaffer A}",
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TY - JOUR

T1 - YAP1-mediated CDK6 activation confers radiation resistance in esophageal cancer – Rationale for the combination of YAP1 and CDK4/6 inhibitors in esophageal cancer

AU - Li, Fan

AU - Xu, Yan

AU - Liu, Bovey

AU - Singh, Pankaj Kumar

AU - Zhao, Wei

AU - Jin, Jiankang

AU - Han, Guangchun

AU - Scott, Ailing W.

AU - Dong, Xiaochuan

AU - Huo, Longfei

AU - Ma, Lang

AU - Pizzi, Melissa Pool

AU - Wang, Ying

AU - Li, Yuan

AU - Harada, Kazuto

AU - Xie, Min

AU - Skinner, Heath

AU - Ding, Sheng

AU - Wang, Linghua

AU - Krishnan, Sunil

AU - Johnson, Randy L

AU - Song, Shumei

AU - Ajani, Jaffer A

PY - 2019/4/1

Y1 - 2019/4/1

N2 - Purpose: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo. Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/ YAP1 high esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1 þ and CD133 þ ), sensitized cells to irradiation, and showed a strong antitumor effect in vivo against radiation-resistant esophageal cancer cells. Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.

AB - Purpose: Esophageal cancer is a lethal disease that is often resistant to therapy. Alterations of YAP1 and CDK6 are frequent in esophageal cancer. Deregulation of both molecules may be responsible for therapy resistance. Experimental Design: Expressions of YAP1 and CDK6 were examined in esophageal cancer cells and tissues using immunoblotting and immunohistochemistry. YAP1 expression was induced in esophageal cancer cells to examine YAP1-mediated CDK6 activation and its association with radiation resistance. Pharmacologic and genetic inhibitions of YAP1 and CDK6 were performed to dissect the mechanisms and assess the antitumor effects in vitro and in vivo. Results: YAP1 expression was positively associated with CDK6 expression in resistant esophageal cancer tissues and cell lines. YAP1 overexpression upregulated CDK6 expression and transcription, and promoted radiation resistance, whereas treatment with the YAP1 inhibitor, CA3, strongly suppressed YAP1 and CDK6 overexpression, reduced Rb phosphorylation, as well as sensitized radiation-resistant/ YAP1 high esophageal cancer cells to irradiation. CDK4/6 inhibitor, LEE011, and knock down of CDK6 dramatically inhibited expression of YAP1 and sensitized resistant esophageal cancer cells to irradiation indicating a positive feed-forward regulation of YAP1 by CDK6. In addition, suppression of both the YAP1 and CDK6 pathways by the combination of CA3 and LEE011 significantly reduced esophageal cancer cell growth and cancer stem cell population (ALDH1 þ and CD133 þ ), sensitized cells to irradiation, and showed a strong antitumor effect in vivo against radiation-resistant esophageal cancer cells. Conclusions: Our results document that a positive crosstalk between the YAP1 and CDK6 pathways plays an important role in conferring radiation resistance to esophageal cancer cells. Targeting both YAP1 and CDK6 pathways could be a novel therapeutic strategy to overcome resistance in esophageal cancer.

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DO - 10.1158/1078-0432.CCR-18-1029

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JO - Clinical Cancer Research

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