Abstract PR07: Pancreatic ductal adenocarcinoma requires PI3Kalpha activity to accelerate circulating DNA-positive metastatic disease
Authors: Thibault Benoit , Ramos-Delgado Fernanda , Pons-Tostivint Elvire , Therville Nicole , Reyes-Castellanos Gabriella , Tosolini Marie , Delord Jean-Pierre , Saur Dieter , Carrier Alice , Cordelier Pierre , Basset Céline , Guillermet-Guibert Julie 
Published: December 2020

Pancreatic ductal adenocarcinoma (PDAC) is a paradigmatic model of micrometastatic disease, characterized by both relapse of surgery and failure of long-term disease control with chemotherapies in resected, locally advanced unresectable and metastatic patients. Molecular characterization of large cohorts of PDAC patients failed to identify actionable pathways associated with mutations except for oncogenic Kras, found in more than 80% of all patients. Class I PI3K being a key regulator of both cell survival and cell migration, we questioned if nonmutated PI3K activity downstream oncogenic Kras is a clinically relevant target for this pathology. To achieve this goal, we devised a novel preclinical protocol in a genetically engineered mouse model (GEMM) including a noninvasive monitoring using circulating cell-free DNA (cfDNA) level as a novel biomarker of micrometastatic disease. We previously showed that, downstream Kras, nonmutant ubiquitous PI3Kalpha is crucial for PDAC development. Among all the mRNA expression-based hallmarks of biologic pathways, we now show that PI3K/Akt/mTOR hallmark is significantly increased in PDAC patients with advanced metastatic disease. High scoring of PI3Kalpha activation, based on expression levels of PI3Kalpha-regulated curated genes, is correlated to a poor prognosis, and is found in metastatic PDAC cell lines and in patient-derived ex vivo cultures of locally invasive PDAC cancer cells. When testing global or isoform-selective inhibitors in GEMM and human cell lines, we show that biologically efficient PI3K inhibitors annihilate PI3Kalpha strongly, but not necessarily specifically, among the four class I PI3K isoforms, resulting in Akt2 inactivation. Similar results are obtained with siRNA and in PIK3CA oncogenic cell lines. PI3Kalpha controls pancreatic tumor cell line motility and migration. In a GEMM model of PDAC, mice with high level of cfDNA present a shorter survival and develop a metastatic disease. Genetic or pharmacologic inhibition of PI3Kalpha in these mice decreases tumor volume, metastasis, ascitic fluid development, cfDNA quantity and M2 macrophage infiltration. Here, we used GEMMs to define a cfDNA-positive aggressive subtype of PDAC and identify a pharmacologically actionable prometastatic feature driven by PI3Kalpha. We propose PI3K as a therapeutic strategy to suppress PDAC progression and metastasis by scavenging peritumoral CD206-positive macrophages. Our data demonstrate that PI3K agents could be efficient on micrometastatic disease (measured by cfDNA), resulting in delay on macrometastatic dissemination.

This abstract is also being presented as Poster B04.

Citation Format: Benoit Thibault, Fernanda Ramos-Delgado, Elvire Pons-Tostivint, Nicole Therville, Gabriella Reyes-Castellanos, Marie Tosolini, Jean-Pierre Delord, Dieter Saur, Alice Carrier, Pierre Cordelier, Céline Basset, Julie Guillermet-Guibert. Pancreatic ductal adenocarcinoma requires PI3Kalpha activity to accelerate circulating DNA-positive metastatic disease [abstract]. In: Proceedings of the AACR Special Conference on Targeting PI3K/mTOR Signaling; 2018 Nov 30-Dec 8; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Res 2020;18(10_Suppl):Abstract nr PR07.