Data from <i>Drosophila</i> Screening Identifies Dual Inhibition of MEK and AURKB as an Effective Therapy for Pancreatic Ductal Adenocarcinoma

Abstract

&lt;div&gt;Abstract&lt;p&gt;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 &lt;i&gt;Drosophila&lt;/i&gt; model mimicking the genetic signature in PDAC (&lt;i&gt;KRAS&lt;/i&gt;, &lt;i&gt;TP53&lt;/i&gt;, &lt;i&gt;CDKN2A&lt;/i&gt;, and &lt;i&gt;SMAD4&lt;/i&gt; alterations), which is associated with the worst prognosis in patients. The ‘&lt;i&gt;4-hit&lt;/i&gt;’ 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.&lt;/p&gt;Significance:&lt;p&gt;Development of a &lt;i&gt;Drosophila&lt;/i&gt; 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.&lt;/p&gt;&lt;/div&gt;