Selective multi-kinase inhibition sensitizes mesenchymal pancreatic cancer to immune checkpoint blockade by remodeling the tumor microenvironment

Chiara Falcomatà #, Stefanie Bärthel #, Sebastian A Widholz, Christian Schneeweis, Juan José Montero, Albulena Toska, Jonas Mir, Thorsten Kaltenbacher, Jeannine Heetmeyer, Jonathan J Swietlik, Jing-Yuan Cheng, Bianca Teodorescu, Oliver Reichert, Constantin Schmitt, Kathrin Grabichler, Andrea Coluccio, Fabio Boniolo, Christian Veltkamp, Magdalena Zukowska, Angelica Arenas Vargas, Woo Hyun Paik, Moritz Jesinghaus, Katja Steiger, Roman Maresch, Rupert Öllinger, Tim Ammon, Olga Baranov, Maria S Robles, Julia Rechenberger, Bernhard Kuster, Felix Meissner, Maximilian Reichert, Michael Flossdorf, Roland Rad, Marc Schmidt-Supprian, Günter Schneider, Dieter Saur

.2022 doi: 10.1038/s43018-021-00326-1


KRAS-mutant pancreatic ductal adenocarcinoma (PDAC) is highly immunosuppressive and resistant to targeted and immunotherapies. Among the different PDAC subtypes, basal-like mesenchymal PDAC, which is driven by allelic imbalance, increased gene dosage and subsequent high expression levels of oncogenic KRAS, shows the most aggressive phenotype and strongest therapy resistance. In the present study, we performed a systematic high-throughput combination drug screen and identified a synergistic interaction between the MEK inhibitor trametinib and the multi-kinase inhibitor nintedanib, which targets KRAS-directed oncogenic signaling in mesenchymal PDAC. This combination treatment induces cell-cycle arrest and cell death, and initiates a context-dependent remodeling of the immunosuppressive cancer cell secretome. Using a combination of single-cell RNA-sequencing, CRISPR screens and immunophenotyping, we show that this combination therapy promotes intratumor infiltration of cytotoxic and effector T cells, which sensitizes mesenchymal PDAC to PD-L1 immune checkpoint inhibition. Overall, our results open new avenues to target this aggressive and therapy-refractory mesenchymal PDAC subtype.