Open AccessAugmentation of the therapeutic efficacy of WEE 1 kinase inhibitor AZD 1775 by inhibiting the YAP –E2F1– DNA damage response pathway axis
Author(s) -
Oku Yusuke,
Nishiya Naoyuki,
Tazawa Takaaki,
Kobayashi Takaya,
Umezawa Nanami,
Sugawara Yasuyo,
Uehara Yoshimasa
Publication year - 2018
Publication title -
febs open bio
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.718
H-Index - 31
ISSN - 2211-5463
DOI - 10.1002/2211-5463.12440
Subject(s) - dasatinib , cancer research , dna damage , plk1 , kinase , microbiology and biotechnology , e2f1 , hippo signaling pathway , effector , cell cycle , cell cycle checkpoint , cancer , biology , chemistry , signal transduction , dna , tyrosine kinase , genetics
The main reasons for failure of cancer chemotherapy are intrinsic and acquired drug resistance. The Hippo pathway effector Yes‐associated protein ( YAP ) is associated with resistance to both cytotoxic and molecular targeted drugs. Several lines of evidence indicate that YAP activates transcriptional programmes to promote cell cycle progression and DNA damage responses. Therefore, we hypothesised that YAP is involved in the sensitivity of cancer cells to small‐molecule agents targeting cell cycle‐related proteins. Here, we report that the inactivation of YAP sensitises the OVCAR ‐8 ovarian cancer cell line to AZD 1775, a small‐molecule WEE 1 kinase inhibitor. The accumulation of DNA damage and mitotic failures induced by AZD 1775‐based therapy were further enhanced by YAP depletion. YAP depletion reduced the expression of the Fanconi anaemia ( FA ) pathway components required for DNA repair and their transcriptional regulator E2F1. These results suggest that YAP activates the DNA damage response pathway, exemplified by the FA pathway and E2F1. Furthermore, we aimed to apply this finding to combination chemotherapy against ovarian cancers. The regimen containing dasatinib, which inhibits the nuclear localisation of YAP , improved the response to AZD 1775‐based therapy in the OVCAR ‐8 ovarian cancer cell line. We propose that dasatinib acts as a chemosensitiser for a subset of molecular targeted drugs, including AZD 1775, by targeting YAP .