Hypersensitivities for acetaldehyde and other agents among cancer cells null for clinically relevant fanconi anemia genes

Soma Ghosh, Surojit Sur, Sashidhar R. Yerram, Carlo Rago, Anil K. Bhunia, M. Zulfiquer Hossain, Bogdan C. Paun, Yunzhao R. Ren, Christine A. Iacobuzio-Donahue, Nilofer A. Azad, Scott E. Kern

Research output: Contribution to journalArticlepeer-review

Abstract

Large-magnitude numerical distinctions (>10-fold) among drug responses of genetically contrasting cancers were crucial for guiding the development of some targeted therapies. Similar strategies brought epidemiological clues and prevention goals for genetic diseases. Such numerical guides, however, were incomplete or low magnitude for Fanconi anemia pathway (FANC) gene mutations relevant to cancer in FANC-mutation carriers (heterozygotes). We generated a four-gene FANC-null cancer panel, including the engineering of new PALB2/FANCN-null cancer cells by homologous recombination. A characteristic matching of FANCC-null, FANCG-null, BRCA2/FANCD1-null, and PALB2/FANCN-null phenotypes was confirmed by uniform tumor regression on single-dose cross-linker therapy in mice and by shared chemical hypersensitivities to various inter-strand cross-linking agents and γ-radiation in vitro. Some compounds, however, had contrasting magnitudes of sensitivity; a strikingly high (19- to 22-fold) hypersensitivity was seen among PALB2-null and BRCA2-null cells for the ethanol metabolite, acetaldehyde, associated with widespread chromosomal breakage at a concentration not producing breaks in parental cells. Because FANC-defective cancer cells can share or differ in their chemical sensitivities, patterns of selective hypersensitivity hold implications for the evolutionary understanding of this pathway. Clinical decisions for cancer-relevant prevention and management of FANC-mutation carriers could be modified by expanded studies of high-magnitude sensitivities.

Original languageEnglish (US)
Pages (from-to)260-270
Number of pages11
JournalAmerican Journal of Pathology
Volume184
Issue number1
DOIs
StatePublished - Jan 2014

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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