MAPK-pathway inhibition mediates inflammatory reprogramming and sensitizes tumors to targeted activation of innate immunity sensor RIG-I

Johannes Brägelmann,Reinhard Büttner,Joshua D’Rozario,Julie George,Jan Förster ,Marija Trajkovic‐Arsic ,S Lennartz ,Emily Simon Thomas ,David Ast ,Laura Godfrey ,M Schmiel ,Junjie Gu ,Jenny Ostendorp,Clemens A Schmitt,Philipp Lohneis,Sachi Okawa,Sven Borchmann,Silvia Von Karstedt,Atsuko Hirabae,Roman K Thomas,Kazuya Nishii,Dennis Plenker,Sebastian Klein,Lydia Meder,Jens T Siveke,Roland T Ullrich,Kadoaki Ohashi,Henry Li,Thomas Zillinger,Julia Wegner,Marcel A Dammert,Carina Lorenz,Alexander Quaas,Martin Schlee,Mareike Haarmann,Gunther Hartmann,Alena Heimsoeth,Takamasa Nakasuka,Martin L Sos

doi:10.1038/s41467-021-25728-8

Abstract

Kinase inhibitors suppress the growth of oncogene driven cancer but also enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. Here, we report transcriptomic and functional genomics analyses of cells and tumors within their microenvironment across different genotypes that persist during kinase inhibitor treatment. We uncover a conserved, MAPK/IRF1-mediated inflammatory response in tumors that undergo stemness- and senescence-associated reprogramming. In these tumor cells, activation of the innate immunity sensor RIG-I via its agonist IVT4, triggers an interferon and a pro-apoptotic response that synergize with concomitant kinase inhibition. In humanized lung cancer xenografts and a syngeneic Egfr-driven lung cancer model these effects translate into reduction of exhausted CD8+ T cells and robust tumor shrinkage. Overall, the mechanistic understanding of MAPK/IRF1-mediated intratumoral reprogramming may ultimately prolong the efficacy of targeted drugs in genetically defined cancer patients.

Highlights

Kinase inhibitors suppress the growth of oncogene driven cancer and enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients
The advent of precision medicine aiming at oncogenic mutations in kinases like EGFR and BRAF led to a significant improvement of the overall survival across different tumor types[1,2,3]
We observed a shared induction of Interferon (IFN) target gene sets[13,14] and an adult tissue stem-cell gene signature (ATSC)[27], which has recently been associated with therapy-induced senescence in the joint analysis (Fig. 1a)[28]

Summary

Introduction

Kinase inhibitors suppress the growth of oncogene driven cancer and enforce the selection of treatment resistant cells that are thought to promote tumor relapse in patients. It has been shown that compounds such as cyclin-dependent kinase (CDK) inhibitors and epigenetic drugs may have the capacity to evoke similar effects through the induction of inflammation in the tumor-microenvironment[11,13,14,15,16,17] These effects were in part explained by the engagement of nucleic acid receptors (NARs) and their downstream STING- or MAVSdependent innate immunity pathways[13,14,15,18,19]. NARs like cGAS, MDA5, TLR3, or RIG-I (DDX58) are conserved proteins of the cellular innate immune system aiming to recognize foreign nucleic acids e.g. following a virus infection to induce cell death or improved immune recognition[20,21] Exploiting their role in stimulating immune recognition, NAR agonists have been used successfully to promote response to immunotherapies[22,23]. We show that the RIG-I agonist IVT4 exploits the reprogrammed drugtolerant state and limits the outgrowth of oncogene-dependent tumor types in vitro and invivo

Objectives

Methods

Results

Conclusion