Combined AURKA and H3K9 methyltransferase targeting inhibits cell growth by inducing mitotic catastrophe

Angela Mathison, Ann Salmonson, Mckenna Missfeldt, Jennifer Bintz, Monique Williams, Sarah Kossak, Asha Nair, Thiago M. De Assuncao, Trace Christensen, Navtej Singh Buttar, Juan Iovanna, Robert C Huebert, Gwen Lomberk

Research output: Contribution to journalArticle

5 Citations (Scopus)

Abstract

The current integrative pathobiologic hypothesis states that pancreatic cancer (PDAC) develops and progresses in response to an interaction between known oncogenes and downstream epigenomic regulators. Congruently, this study tests a new combinatorial therapy based on the inhibition of the Aurora kinase A (AURKA) oncogene and one of its targets, the H3K9 methylation-based epigenetic pathway. This therapeutic combination is effective at inhibiting the in vitro growth of PDAC cells both, in monolayer culture systems, and in three-dimensional spheroids and organoids. The combination also reduces the growth of PDAC xenografts in vivo. Mechanistically, it was found that inhibiting methyltransferases of the H3K9 pathway in cells, which are arrested in G2-M after targeting AURKA, decreases H3K9 methylation at centromeres, induces mitotic aberrations, triggers an aberrant mitotic check point response, and ultimately leads to mitotic catastrophe. Combined, these data describe for the first time a hypothesis-driven design of an efficient combinatorial treatment that targets a dual oncogenic-epigenomic pathway to inhibit PDAC cell growth via a cytotoxic mechanism that involves perturbation of normal mitotic progression to end in mitotic catastrophe. Therefore, this new knowledge has significant mechanistic value as it relates to the development of new therapies as well as biomedical relevance.

Original languageEnglish (US)
Pages (from-to)984-997
Number of pages14
JournalMolecular Cancer Research
Volume15
Issue number8
DOIs
StatePublished - Aug 1 2017

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Aurora Kinase A
Methyltransferases
Epigenomics
Oncogenes
Methylation
Growth
Organoids
Centromere
Pancreatic Neoplasms
Heterografts
Therapeutics

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

Cite this

Mathison, A., Salmonson, A., Missfeldt, M., Bintz, J., Williams, M., Kossak, S., ... Lomberk, G. (2017). Combined AURKA and H3K9 methyltransferase targeting inhibits cell growth by inducing mitotic catastrophe. Molecular Cancer Research, 15(8), 984-997. https://doi.org/10.1158/1541-7786.MCR-17-0063

Combined AURKA and H3K9 methyltransferase targeting inhibits cell growth by inducing mitotic catastrophe. / Mathison, Angela; Salmonson, Ann; Missfeldt, Mckenna; Bintz, Jennifer; Williams, Monique; Kossak, Sarah; Nair, Asha; De Assuncao, Thiago M.; Christensen, Trace; Buttar, Navtej Singh; Iovanna, Juan; Huebert, Robert C; Lomberk, Gwen.

In: Molecular Cancer Research, Vol. 15, No. 8, 01.08.2017, p. 984-997.

Research output: Contribution to journalArticle

Mathison, A, Salmonson, A, Missfeldt, M, Bintz, J, Williams, M, Kossak, S, Nair, A, De Assuncao, TM, Christensen, T, Buttar, NS, Iovanna, J, Huebert, RC & Lomberk, G 2017, 'Combined AURKA and H3K9 methyltransferase targeting inhibits cell growth by inducing mitotic catastrophe', Molecular Cancer Research, vol. 15, no. 8, pp. 984-997. https://doi.org/10.1158/1541-7786.MCR-17-0063
Mathison, Angela ; Salmonson, Ann ; Missfeldt, Mckenna ; Bintz, Jennifer ; Williams, Monique ; Kossak, Sarah ; Nair, Asha ; De Assuncao, Thiago M. ; Christensen, Trace ; Buttar, Navtej Singh ; Iovanna, Juan ; Huebert, Robert C ; Lomberk, Gwen. / Combined AURKA and H3K9 methyltransferase targeting inhibits cell growth by inducing mitotic catastrophe. In: Molecular Cancer Research. 2017 ; Vol. 15, No. 8. pp. 984-997.
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