Modulating environmental signals to reveal mechanisms and vulnerabilities of cancer persisters

Abstract

Cancer persister cells are able to survive otherwise lethal doses of drugs through nongenetic mechanisms, which can lead to cancer regrowth and drug resistance. The broad spectrum of molecular differences observed between persisters and their treatment-naïve counterparts makes it challenging to identify causal mechanisms underlying persistence. Here, we modulate environmental signals to identify cellular mechanisms that promote the emergence of persisters and to pinpoint actionable vulnerabilities that eliminate them. We found that interferon-γ (IFNγ) can induce a pro-persistence signal that can be specifically eliminated by inhibition of type I protein arginine methyltransferase (PRMT) (PRMTi). Mechanistic investigation revealed that signal transducer and activator of transcription 1 (STAT1) is a key component connecting IFNγ’s pro-persistence and PRMTi’s antipersistence effects, suggesting a previously unknown application of PRMTi to target persisters in settings with high STAT1 expression. Modulating environmental signals can accelerate the identification of mechanisms that promote and eliminate cancer persistence.

H3K4me3 remodeling induced acquired resistance through O-GlcNAc transferase

“…Together, co-targeting oncogenic drivers and mediators of stress-induced cellular reprogramming like OGT could trap cells in a slow-cycling persister state, preventing the development of permanent acquired drug resistance and disease relapse. The vulnerabilities of cancer persisters could then be either directly targeted ( Zou et al, 2019 , Sun et al, 2022 ) or the reversibility of the phenotype could be exploited through scheduled treatment interruption and re-challenge ( Schreuer et al, 2017 ). While the mechanistic details of the epigenetic reprogramming and stabilization as well as the specific contribution of the OGT/TET1/H3K4me3 complex-mediated transcriptional programs remain to be elucidated, this work identified a novel mechanism of epigenetic reprogramming that can be targeted to inhibit cancer plasticity and adaption, ultimately prolonging treatment success of current standard of care.…”