TY - JOUR
T1 - Combined AURKA and H3K9 methyltransferase targeting inhibits cell growth by inducing mitotic catastrophe
AU - Mathison, Angela
AU - Salmonson, Ann
AU - Missfeldt, Mckenna
AU - Bintz, Jennifer
AU - Williams, Monique
AU - Kossak, Sarah
AU - Nair, Asha
AU - De Assuncao, Thiago M.
AU - Christensen, Trace
AU - Buttar, Navtej
AU - Iovanna, Juan
AU - Huebert, Robert
AU - Lomberk, Gwen
N1 - Publisher Copyright:
©2017 AACR.
PY - 2017/8
Y1 - 2017/8
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85026643394&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85026643394&partnerID=8YFLogxK
U2 - 10.1158/1541-7786.MCR-17-0063
DO - 10.1158/1541-7786.MCR-17-0063
M3 - Article
C2 - 28442587
AN - SCOPUS:85026643394
SN - 1541-7786
VL - 15
SP - 984
EP - 997
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 8
ER -