Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma

Background and Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathog...

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Main Authors: Stefanie S. Schalm, Erin O’Hearn, Kevin Wilson, Timothy P. LaBranche, Grace Silva, Zhuo Zhang, Lucian DiPietro, Neil Bifulco, Richard Woessner, Nicolas Stransky, Darshan Sappal, Robert Campbell, Riadh Lobbardi, Michael Palmer, Joseph Kim, Chaoyang Ye, Marion Dorsch, Christoph Lengauer, Timothy Guzi, Vivek Kadambi, Andrew Garner, Klaus P. Hoeflich
Format: Article
Language:English
Published: Elsevier 2023-01-01
Series:Gastro Hep Advances
Subjects:
Online Access:http://www.sciencedirect.com/science/article/pii/S2772572322001911
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author Stefanie S. Schalm
Erin O’Hearn
Kevin Wilson
Timothy P. LaBranche
Grace Silva
Zhuo Zhang
Lucian DiPietro
Neil Bifulco
Richard Woessner
Nicolas Stransky
Darshan Sappal
Robert Campbell
Riadh Lobbardi
Michael Palmer
Joseph Kim
Chaoyang Ye
Marion Dorsch
Christoph Lengauer
Timothy Guzi
Vivek Kadambi
Andrew Garner
Klaus P. Hoeflich
author_facet Stefanie S. Schalm
Erin O’Hearn
Kevin Wilson
Timothy P. LaBranche
Grace Silva
Zhuo Zhang
Lucian DiPietro
Neil Bifulco
Richard Woessner
Nicolas Stransky
Darshan Sappal
Robert Campbell
Riadh Lobbardi
Michael Palmer
Joseph Kim
Chaoyang Ye
Marion Dorsch
Christoph Lengauer
Timothy Guzi
Vivek Kadambi
Andrew Garner
Klaus P. Hoeflich
author_sort Stefanie S. Schalm
collection DOAJ
description Background and Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods: FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as previously. Results: Knockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment vs control (P = .003 and P = .0005, respectively). Conclusion: We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.
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spelling doaj.art-2154c1b576ce47429fad42ed3d908a8f2023-04-20T04:37:56ZengElsevierGastro Hep Advances2772-57232023-01-0123307321Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar CarcinomaStefanie S. Schalm0Erin O’Hearn1Kevin Wilson2Timothy P. LaBranche3Grace Silva4Zhuo Zhang5Lucian DiPietro6Neil Bifulco7Richard Woessner8Nicolas Stransky9Darshan Sappal10Robert Campbell11Riadh Lobbardi12Michael Palmer13Joseph Kim14Chaoyang Ye15Marion Dorsch16Christoph Lengauer17Timothy Guzi18Vivek Kadambi19Andrew Garner20Klaus P. Hoeflich21Correspondence: Address correspondence to: Stefanie S. Schalm, Blueprint Medicines Corporation, 45 Sidney Street, Cambridge, Massachusetts 02139.; Blueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBlueprint Medicines Corporation, Cambridge, MassachusettsBackground and Aims: Fibrolamellar carcinoma (FLC) is a rare, difficult-to-treat liver cancer primarily affecting pediatric and adolescent patients, and for which precision medicine approaches have historically not been possible. The DNAJB1-PRKACA gene fusion was identified as a driver of FLC pathogenesis. We aimed to assess whether FLC tumors maintain dependency on this gene fusion and determine if PRKACA is a viable therapeutic target. Methods: FLC patient-derived xenograft (PDX) shRNA cell lines were implanted subcutaneously into female NOD-SCID mice and tumors were allowed to develop prior to randomization to doxycycline (to induce knockdown) or control groups. Tumor development was assessed every 2 days. To assess the effect of treatment with novel selective PRKACA small molecule kinase inhibitors, BLU0588 and BLU2864, FLC PDX tumor cells were implanted subcutaneously into NOD-SCID mice and tumors allowed to develop. Mice were randomized to treatment (BLU0588 and BLU2864, orally, once daily) or control groups and tumor size determined as previously. Results: Knockdown of DNAJB1-PRKACA reversed a FLC-specific gene signature and reduced PDX tumor growth in mice compared to the control group. Furthermore, FLC PDX tumor growth was significantly reduced with BLU0588 and BLU2864 treatment vs control (P = .003 and P = .0005, respectively). Conclusion: We demonstrated, using an inducible knockdown and small molecule approaches, that FLC PDX tumors were dependent upon DNAJB1-PRKACA fusion activity. In addition, this study serves as a proof-of-concept that PRKACA is a viable therapeutic target for FLC and warrants further investigation.http://www.sciencedirect.com/science/article/pii/S2772572322001911Fibrolamellar carcinomaPRKACADNAJB1-PRKACAKinase inhibitor
spellingShingle Stefanie S. Schalm
Erin O’Hearn
Kevin Wilson
Timothy P. LaBranche
Grace Silva
Zhuo Zhang
Lucian DiPietro
Neil Bifulco
Richard Woessner
Nicolas Stransky
Darshan Sappal
Robert Campbell
Riadh Lobbardi
Michael Palmer
Joseph Kim
Chaoyang Ye
Marion Dorsch
Christoph Lengauer
Timothy Guzi
Vivek Kadambi
Andrew Garner
Klaus P. Hoeflich
Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma
Gastro Hep Advances
Fibrolamellar carcinoma
PRKACA
DNAJB1-PRKACA
Kinase inhibitor
title Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma
title_full Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma
title_fullStr Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma
title_full_unstemmed Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma
title_short Evaluation of Protein Kinase cAMP-Activated Catalytic Subunit Alpha as a Therapeutic Target for Fibrolamellar Carcinoma
title_sort evaluation of protein kinase camp activated catalytic subunit alpha as a therapeutic target for fibrolamellar carcinoma
topic Fibrolamellar carcinoma
PRKACA
DNAJB1-PRKACA
Kinase inhibitor
url http://www.sciencedirect.com/science/article/pii/S2772572322001911
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