Chromosomal instability (CIN), a hallmark of cancer, drives cancer cell evolution, metastasis and therapy resistance, and is associated with poor patient prognosis. CIN leads to the formation of micronuclei, which upon rupture spill DNA into the cytoplasm, triggering activation of cGAS/STING inflammatory signalling. cGAS and STING are generally considered to be tumour suppressors as they promote apoptosis and immunosurveillance. However, cGAS and STING are rarely inactivated in cancer, and while they have been implicated in metastasis, it is not known why loss-of-function mutations do not arise in primary tumours. Here, we show that inactivation of cGAS/STING signalling selectively impairs the survival of triple negative breast cancer (TNBC) cells that display CIN. We find that CIN triggers IL6/STAT3-mediated signalling, which depends on cGAS/STING and the non-canonical NF-kB pathway. Blocking IL6 signalling through the clinically-approved IL6R-targeting agent tocilizumab selectively impairs the growth of cultured TNBC cells that exhibit CIN and significantly delays the outgrowth of chromosomally instable tumours compared to tumours that do not display CIN. Importantly, we find that this targetable vulnerability is conserved across cancer types that express high levels of IL6 and/or IL6R in vitro as well as in vivo. Altogether, our work demonstrates pro-tumourigenic traits of cGAS/STING signalling, explaining why the cGAS/STING pathway is rarely inactivated in primary tumours, and exposes a targetable vulnerability of cancers with a CIN phenotype by repurposing tocilizumab for the treatment of chromosomally instable cancers that overexpress IL6R.

This repository contains analysis code, but we are still in the process of cleaning it up.