CDK7 is a Novel Therapeutic Vulnerability in Fibrolamellar Carcinoma

Nukaya, M.; Cafferty, C.; Zahed, K.; Yun, I.; Al-Adra, D. P.; Kazim, N. A.; Farghli, A. R.; Chan, M.; Kratz, J. D.; Berres, M. E.; Yen, A.; Gujral, T.; Sethupathy, P.; Bradfield, C. A.; Ronnekleiv-Kelly, S. M.

doi:10.1101/2023.04.22.537934

bioRxiv · 10.1101/2023.04.22.537934

CDK7 is a Novel Therapeutic Vulnerability in Fibrolamellar Carcinoma

Nukaya, M.·Cafferty, C.·Zahed, K.·Yun, I.·Al-Adra, D. P.·Kazim, N. A.·Farghli, A. R.·Chan, M.·Kratz, J. D.·Berres, M. E.·Yen, A.·Gujral, T.·Sethupathy, P.·Bradfield, C. A.·Ronnekleiv-Kelly, S. M.

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Abstract

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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Nukaya, M., Cafferty, C., Zahed, K., Yun, I., Al-Adra, D. P., Kazim, N. A., Farghli, A. R., Chan, M., Kratz, J. D., Berres, M. E., Yen, A., Gujral, T., Sethupathy, P., Bradfield, C. A., Ronnekleiv-Kelly, S. M.. 2023-04-23. CDK7 is a Novel Therapeutic Vulnerability in Fibrolamellar Carcinoma. https://doi.org/10.1101/2023.04.22.537934

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