PAXIP1 potentiates the combination of WEE1 inhibitor AZD1775 and platinum agents in lung cancer

Ankita Jhuraney, Nicholas T. Woods, Gabriela Wright, Lily Rix, Fumi Kinose, Jodi L. Kroeger, Elizabeth Remily-Wood, W. Douglas Cress, John M. Koomen, Stephen G. Brantley, Jhanelle E. Gray, Eric B. Haura, Uwe Rix, Alvaro N. Monteiro

Research output: Contribution to journalArticle

12 Scopus citations

Abstract

The DNA damage response (DDR) involves a complex network of signaling events mediated by modular protein domains such as the BRCA1 C-terminal (BRCT) domain. Thus, proteins that interact with BRCT domains and are a part of the DDR constitute potential targets for sensitization to DNA-damaging chemotherapy agents. We performed a pharmacologic screen to evaluate 17 kinases, identified in a BRCTmediated interaction network as targets to enhance platinumbased chemotherapy in lung cancer. Inhibition of mitotic kinase WEE1 was found to have the most effective response in combination with platinum compounds in lung cancer cell lines. In the BRCT-mediated interaction network, WEE1 was found in complex with PAXIP1, a protein containing six BRCT domains involved in transcription and in the cellular response to DNA damage. We show that PAXIP1 BRCT domains regulate WEE1-mediated phosphorylation of CDK1. Furthermore, ectopic expression of PAXIP1 promotes enhanced caspase-3-mediated apoptosis in cells treated with WEE1 inhibitor AZD1775 (formerly, MK-1775) and cisplatin compared with cells treated with AZD1775 alone. Cell lines and patientderived xenograft models expressing both PAXIP1 and WEE1 exhibited synergistic effects of AZD1775 and cisplatin. In summary, PAXIP1 is involved in sensitizing lung cancer cells to the WEE1 inhibitor AZD1775 in combination with platinum-based treatment. We propose that WEE1 and PAXIP1 levels may be used as mechanism-based biomarkers of response when WEE1 inhibitor AZD1775 is combined with DNA-damaging agents.

Original languageEnglish (US)
Pages (from-to)1669-1681
Number of pages13
JournalMolecular cancer therapeutics
Volume15
Issue number7
DOIs
StatePublished - Jul 2016

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'PAXIP1 potentiates the combination of WEE1 inhibitor AZD1775 and platinum agents in lung cancer'. Together they form a unique fingerprint.

  • Cite this

    Jhuraney, A., Woods, N. T., Wright, G., Rix, L., Kinose, F., Kroeger, J. L., Remily-Wood, E., Cress, W. D., Koomen, J. M., Brantley, S. G., Gray, J. E., Haura, E. B., Rix, U., & Monteiro, A. N. (2016). PAXIP1 potentiates the combination of WEE1 inhibitor AZD1775 and platinum agents in lung cancer. Molecular cancer therapeutics, 15(7), 1669-1681. https://doi.org/10.1158/1535-7163.MCT-15-0182