Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma

Julien Bollard, Verónica Miguela, Marina Ruiz De Galarreta, Anu Venkatesh, C. Billie Bian, Mark P. Roberto, Victoria Tovar, Daniela Sia, Pedro Molina-Sánchez, Christie B. Nguyen, Shigeki Nakagawa, Josep M. Llovet, Yujin Hoshida, Amaia Lujambio

Research output: Contribution to journalArticle

46 Citations (Scopus)

Abstract

Objective Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. Design The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses. Results Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of 'RB1 loss of function' was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival. Conclusions Palbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.

Original languageEnglish (US)
Pages (from-to)1286-1296
Number of pages11
JournalGut
Volume66
Issue number7
DOIs
StatePublished - Jul 1 2017
Externally publishedYes

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Hepatocellular Carcinoma
Growth
Neoplasms
Liver Neoplasms
Cell Line
palbociclib
Cell Proliferation
Therapeutics
Retinoblastoma
Cell Aging
Standard of Care
Cell Cycle Checkpoints
Heterografts
Cell Death
Breast Neoplasms
Gene Expression
Survival

Keywords

  • CELL CYCLE
  • HEPATOCELLULAR CARCINOMA

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Bollard, J., Miguela, V., Ruiz De Galarreta, M., Venkatesh, A., Bian, C. B., Roberto, M. P., ... Lujambio, A. (2017). Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. Gut, 66(7), 1286-1296. https://doi.org/10.1136/gutjnl-2016-312268

Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. / Bollard, Julien; Miguela, Verónica; Ruiz De Galarreta, Marina; Venkatesh, Anu; Bian, C. Billie; Roberto, Mark P.; Tovar, Victoria; Sia, Daniela; Molina-Sánchez, Pedro; Nguyen, Christie B.; Nakagawa, Shigeki; Llovet, Josep M.; Hoshida, Yujin; Lujambio, Amaia.

In: Gut, Vol. 66, No. 7, 01.07.2017, p. 1286-1296.

Research output: Contribution to journalArticle

Bollard, J, Miguela, V, Ruiz De Galarreta, M, Venkatesh, A, Bian, CB, Roberto, MP, Tovar, V, Sia, D, Molina-Sánchez, P, Nguyen, CB, Nakagawa, S, Llovet, JM, Hoshida, Y & Lujambio, A 2017, 'Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma', Gut, vol. 66, no. 7, pp. 1286-1296. https://doi.org/10.1136/gutjnl-2016-312268
Bollard, Julien ; Miguela, Verónica ; Ruiz De Galarreta, Marina ; Venkatesh, Anu ; Bian, C. Billie ; Roberto, Mark P. ; Tovar, Victoria ; Sia, Daniela ; Molina-Sánchez, Pedro ; Nguyen, Christie B. ; Nakagawa, Shigeki ; Llovet, Josep M. ; Hoshida, Yujin ; Lujambio, Amaia. / Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma. In: Gut. 2017 ; Vol. 66, No. 7. pp. 1286-1296.
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abstract = "Objective Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. Design The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses. Results Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of 'RB1 loss of function' was found in <30{\%} of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival. Conclusions Palbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70{\%} of all patients with HCC.",
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T1 - Palbociclib (PD-0332991), a selective CDK4/6 inhibitor, restricts tumour growth in preclinical models of hepatocellular carcinoma

AU - Bollard, Julien

AU - Miguela, Verónica

AU - Ruiz De Galarreta, Marina

AU - Venkatesh, Anu

AU - Bian, C. Billie

AU - Roberto, Mark P.

AU - Tovar, Victoria

AU - Sia, Daniela

AU - Molina-Sánchez, Pedro

AU - Nguyen, Christie B.

AU - Nakagawa, Shigeki

AU - Llovet, Josep M.

AU - Hoshida, Yujin

AU - Lujambio, Amaia

PY - 2017/7/1

Y1 - 2017/7/1

N2 - Objective Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. Design The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses. Results Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of 'RB1 loss of function' was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival. Conclusions Palbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.

AB - Objective Advanced hepatocellular carcinoma (HCC) is a lethal malignancy with limited treatment options. Palbociclib, a well-tolerated and selective CDK4/6 inhibitor, has shown promising results in the treatment of retinoblastoma (RB1)-positive breast cancer. RB1 is rarely mutated in HCC, suggesting that palbociclib could potentially be used for HCC therapy. Here, we provide a comprehensive characterisation of the efficacy of palbociclib in multiple preclinical models of HCC. Design The effects of palbociclib on cell proliferation, cellular senescence and cell death were investigated in a panel of human liver cancer cell lines, in ex vivo human HCC samples, in a genetically engineered mouse model of liver cancer, and in human HCC xenografts in vivo. The mechanisms of intrinsic and acquired resistance to palbociclib were assessed in human liver cancer cell lines and human HCC samples by protein and gene expression analyses. Results Palbociclib suppressed cell proliferation in human liver cancer cell lines by promoting a reversible cell cycle arrest. Intrinsic and acquired resistance to palbociclib was determined by loss of RB1. A signature of 'RB1 loss of function' was found in <30% of HCC samples. Palbociclib, alone or combined with sorafenib, the standard of care for HCC, impaired tumour growth in vivo and significantly increased survival. Conclusions Palbociclib shows encouraging results in preclinical models of HCC and represents a novel therapeutic strategy for HCC treatment, alone or particularly in combination with sorafenib. Palbociclib could potentially benefit patients with RB1-proficient tumours, which account for 70% of all patients with HCC.

KW - CELL CYCLE

KW - HEPATOCELLULAR CARCINOMA

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