Abstract

PURPOSE: G9a histone methyltransferase exerts oncogenic effects in several tumor-types and its inhibition promotes anti-cancer effects. However, the impact on checkpoint inhibitor blockade response and the utility of G9a or its target genes as a biomarker is poorly studied. We aimed to examine whether G9a inhibition can augment the efficacy of checkpoint inhibitor blockade and whether LC3B, a G9a target gene can predict treatment response. EXPERIMENTAL DESIGN: Clinical potential of LC3B as a biomarker of checkpoint inhibitor blockade was assessed using patient samples including tumor biopsies and circulating tumor cells from liquid biopsies. Efficacy of G9a inhibition to enhance checkpoint inhibitor blockade was examined using a mouse model. RESULTS: or LC3B protein was associated with longer survival and lower incidence of acquired resistance to checkpoint inhibitor blockade suggesting LC3B as a potential predictive biomarker. We demonstrate G9a histone methyltransferase inhibition is able to not only robustly induce LC3B level to augment the efficacy of checkpoint inhibitor blockade, but also induces melanoma cell death. CONCLUSIONS: Checkpoint inhibitor blockade response is limited to a subset of patient population. These results have implications for the development of LC3B as a predictive biomarker of checkpoint inhibitor blockade to guide patient selection, as well as G9a inhibition as a strategy to extend the proportion of patients responding to immunotherapy.

Authors	Kelly, Greg; Al-Ejeh, Fares; McCuaig, Robert D; Casciello, Francesco; Kamal, Nabilah; Ferguson, Blake; Pritchard, Antonia L; Ali, Sayed; Silva, Ines; Wilmott, James S; Long, Georgina V; Scolyer, Richard A; Rao, Sudha; Hayward, Nicholas K; Gannon, Frank; Lee, Jason S
Journal	CLINICAL CANCER RESEARCH
Pages	2624-2635
Volume	27
Date	1/01/2021
Grant ID
Funding Body
URL	http://www.ncbi.nlm.nih.gov/pubmed/?term=10.1158/1078-0432.CCR-20-3463