Augmentation of the therapeutic efficacy of WEE1 kinase inhibitor AZD1775 by inhibiting the YAP–E2F1–DNA damage response pathway axis

• Published in: FEBS open bio 2018-06, Vol.8 (6), p.1001-1012
• Main Authors: Oku, Yusuke, Nishiya, Naoyuki, Tazawa, Takaaki, Kobayashi, Takaya, Umezawa, Nanami, Sugawara, Yasuyo, Uehara, Yoshimasa
• Format: Article
• Language: English
• Subjects: AZD1775; combination therapy; dasatinib; DNA damage; YAP
• ISSN: 2211-5463; 2211-5463
• DOI: 10.1002/2211-5463.12440

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 AZD1775, a small‐molecule WEE1 kinase inhibitor. The accumulation of DNA damage and mitotic failures induced by AZD1775‐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 AZD1775‐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 AZD1775, by targeting YAP. Cancer chemotherapy often fails due to intrinsic or acquired drug resistance. YAP inactivation reduces the expression of E2F1 and DNA damage response components exemplified by the Fanconi anaemia pathway components. Under such circumstance, cells cannot tolerate the abrogation of cell cycle arrest by the drug AZD1775 following DNA damage. This results in catastrophic mitosis and cell death.