Drosophila Screening Identifies Dual Inhibition of MEK and AURKB as an Effective Therapy for Pancreatic Ductal Adenocarcinoma

Author:

Sekiya Sho12ORCID,Fukuda Junki12ORCID,Yamamura Ryodai1ORCID,Ooshio Takako1ORCID,Satoh Yusuke1ORCID,Kosuge Shinya12ORCID,Sato Reo1ORCID,Hatanaka Kanako C.3ORCID,Hatanaka Yutaka34ORCID,Mitsuhashi Tomoko5ORCID,Nakamura Toru2ORCID,Matsuno Yoshihiro5ORCID,Hirano Satoshi2ORCID,Sonoshita Masahiro16ORCID

Affiliation:

1. 1Division of Biomedical Oncology, Institute for Genetic Medicine, Hokkaido University, Sapporo, Japan.

2. 2Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Japan.

3. 3Center for Development of Advanced Diagnostics, Hokkaido University Hospital, Sapporo, Japan.

4. 4Research Division of Genome Companion Diagnostics, Hokkaido University Hospital, Sapporo, Japan.

5. 5Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan.

6. 6Global Station for Biosurfaces and Drug Discovery, Hokkaido University, Sapporo, Japan.

Abstract

Abstract Significant progress has been made in understanding the pathogenesis of pancreatic ductal adenocarcinoma (PDAC) by generating and using murine models. To accelerate drug discovery by identifying novel therapeutic targets on a systemic level, here we generated a Drosophila model mimicking the genetic signature in PDAC (KRAS, TP53, CDKN2A, and SMAD4 alterations), which is associated with the worst prognosis in patients. The ‘4-hit’ flies displayed epithelial transformation and decreased survival. Comprehensive genetic screening of their entire kinome revealed kinases including MEK and AURKB as therapeutic targets. Consistently, a combination of the MEK inhibitor trametinib and the AURKB inhibitor BI-831266 suppressed the growth of human PDAC xenografts in mice. In patients with PDAC, the activity of AURKB was associated with poor prognosis. This fly-based platform provides an efficient whole-body approach that complements current methods for identifying therapeutic targets in PDAC. Significance: Development of a Drosophila model mimicking genetic alterations in human pancreatic ductal adenocarcinoma provides a tool for genetic screening that identifies MEK and AURKB inhibition as a potential treatment strategy.

Funder

Japan Society for the Promotion of Science

Japan Agency for Medical Research and Development

Japan Science and Technology Agency

Princess Takamatsu Cancer Research Fund

Akiyama Life Science Foundation

Takeda Science Foundation

MSD Life Science Foundation, Public Interest Incorporated Foundation

Suhara Memorial Foundation

Publisher

American Association for Cancer Research (AACR)

Subject

Cancer Research,Oncology

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