The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma

Bauer, Jens; Stickel, Natalie; Maringer, Yacine; Bucher, Philip; Bilich, Tatjana; Zwick, Melissa; Dicks, Severin; Nelde, Annika; Dubbelaar, Marissa L.; Scheid, Jonas; Wacker, Marcel; Schroeder, Sarah; Rieth, Jonas; Denk, Monika; Richter, Marion; Klein, Reinhild; Bonzheim, Irina; Luibrand, Julia; Holzer, Ursula; Ebinger, Martin; Brecht, Ines B.; Bitzer, Michael; Boerries, Melanie; Feucht, Judith; Salih, Helmut R.; Rammensee, Hans‐Georg; Hailfinger, Stephan; Walz, Juliane S.

doi:10.1038/s41467-022-33746-3

Cited by 23 publications

(33 citation statements)

References 85 publications

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“…In the coming year, we hope to have drugs that are already in the clinic 'repurposed' for FLC. In the near future, there will be therapies targeted directly against the driver 36 or towards recruitment of the immune system 43,46 . Still, it does not feel like a moment to celebrate.…”

Section: Prognosismentioning

confidence: 99%

Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

Simon

2023

Nat Rev Cancer

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The fight against rare cancers faces myriad challenges, including missed or wrong diagnoses, lack of information and diagnostic tools, too few samples and too little funding. Yet many advances in cancer biology, such as the realization that there are tumour suppressor genes, have come from studying well-defined, albeit rare, cancers. Fibrolamellar hepatocellular carcinoma (FLC), a typically lethal liver cancer, mainly affects adolescents and young adults. FLC is both rare, 1 in 5 million, and problematic to diagnose. From the paucity of data, it was not known whether FLC was one cancer or a collection with similar phenotypes, or whether it was genetically inherited or the result of a somatic mutation. A personal journey through a decade of work reveals answers to these questions and a road map of steps and missteps in our fight against a rare cancer.

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Section: Prognosismentioning

confidence: 99%

Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

Simon

2023

Nat Rev Cancer

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“…Moreover, the TIMS provides a new dimension of separation with the CCS value as an additional peptide property, which has been suggested to improve statistical con dence in peptide identi cation. 28,29 In a direct comparison with state-of-the-art immunopeptidomics using orbitrap technology [30][31][32] which lacks ion mobility separation, timsTOF-based immunopeptidomics revealed signi cantly increased HLApresented peptide identi cations from benign and malignant primary samples of solid tissues and hematological cells analyzed after equal sample separation post preparation. This makes timsTOF-based immunopeptidomics attractive for sample-limited applications, such as peptide identi cation from biopsies, micro-dissected tissues, and sorted cell populations.…”

Section: Discussionmentioning

confidence: 99%

“…The orbitrap-based MS analysis was performed as described previously. 30 Peptides were separated by nano ow high-performance liquid chromatography using a Thermo Fisher Scienti c's Ultimate 3000 RSLC Nano UHPLC system, loaded with 1% AcN 0.05% TFA on a 75 µm x 2 cm Acclaim PepMap 100 C18 Nanotrap column at a ow rate of 4 mL/min for 10 min following a separation step using a 50 µm x 25 cm PepMap RSLC C18 column with a particle size of 2 µm. Peptides were eluted at a gradient ranging from 2.4-32% AcN over 90 min.…”

Section: Orbitrap Mass Spectrometric Data Acquisitionmentioning

confidence: 99%

timsTOF mass spectrometry-based immunopeptidomics refines tumor antigen identification

Gravel¹,

Nelde²,

Bauer³

et al. 2023

Preprint

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T cell recognition of human leukocyte antigen (HLA)-presented tumor-associated peptides is central for cancer immune surveillance. Mass spectrometry (MS)-based immunopeptidomics represents the only unbiased method for the direct identification and characterization of naturally presented tumor-associated peptides, a key prerequisite for the development of T cell-based immunotherapies. This study reports on the de novo implementation of ion mobility separation-based timsTOF MS for next-generation immunopeptidomics, enabling high-speed and sensitive detection of HLA-presented peptides. A direct comparison of timsTOF-based with state-of-the-art immunopeptidomics using orbitrap technology showed significantly increased HLA peptide identifications from benign and malignant primary samples of solid tissue and hematological origin. First application of timsTOF-based immunopeptidomics for tumor antigen discovery enabled (i) the expansion of benign reference immunopeptidome databases with > 150,000 HLA-presented peptides from 94 primary benign tissue samples, (ii) the refinement of previously described tumor antigens, and (iii) the identification of a vast array of novel tumor antigens, comprising low abundant neoepitopes, that might serve as targets for future cancer immunotherapy development.

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“…12 Another group exploited the FLC-specific nature (i.e., exclusively in tumor cells) of the immunogenic neoepitopes from the DNAJ-PKAc chimera to pioneer an innovative immune targeting strategy. 13 The authors performed a series of elegant studies to reveal that a personalized chimeric protein-derived peptide vaccine in conjunction with a toll-like receptor 1/2 agonist resulted in sustained immune response in a patient with multiple prior recurrences. However, limitations exist with a vaccine / immunotherapy-based strategy (e.g., patients with autoimmune disorder, immunotherapy-induced toxicity, or lack of induced immune response).…”

Section: Introductionmentioning

confidence: 99%

CDK7 is a Novel Therapeutic Vulnerability in Fibrolamellar Carcinoma

Nukaya

Cafferty

Zahed

et al. 2023

Preprint

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Fibrolamellar carcinoma (FLC) is a rare and lethal cancer that afflicts young individuals. The tumor arises in the background of a healthy liver, and patients typically present with advanced cancer at the time of diagnosis. Unfortunately, for these patients with advanced or recurrent cancer, no proven systemic therapies exist resulting in only 30-45% of patients surviving to 5 years. Investigations into the molecular underpinning of FLC have revealed a unique gene fusion between heat shock protein 40 (DNAJB1) and the catalytic subunit alpha of protein kinase A (PRKACA), leading to the formation of an oncoprotein (DNAJ-PKAc) that retains kinase activity and is a proven tumor-causing event in FLC. To uncover potential therapeutic targets, we engineered an FLC cell line by introducing the DNAJB1-PRKACA oncogene rearrangement into human hepatocellular cells using CRISPR/Cas9. We identified aberrant cell cycle progression, and follow-up molecular analysis revealed evidence of enhanced cyclin dependent kinase 7 (CDK7) activation in the DNAJB1-PRKACA expressing FLC cells. These findings were confirmed in human samples of FLC. In turn, targeting CDK7 with selective inhibitors demonstrated efficacy in several patient-derived models of FLC, with minimal toxicity to normal liver. Collectively, this work uncovers a novel candidate therapeutic vulnerability in FLC.

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The oncogenic fusion protein DNAJB1-PRKACA can be specifically targeted by peptide-based immunotherapy in fibrolamellar hepatocellular carcinoma

Cited by 23 publications

References 85 publications

Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

Fighting rare cancers: lessons from fibrolamellar hepatocellular carcinoma

timsTOF mass spectrometry-based immunopeptidomics refines tumor antigen identification

CDK7 is a Novel Therapeutic Vulnerability in Fibrolamellar Carcinoma

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