Abstract 1727P
Background
Although anti-PD-1/PD-L1 antibodies represent a major breakthrough in NSCLC patients’ survival, this treatment efficacy is highly dependent on tumor PD-L1 expression. We reported the role of Id1 and the efficacy of a combined blockade of PD-1-Id1 in a KRAS mutant NSCLC mouse model [Baraibar, Cancers 2020]. Trametinib, an oral MEK1/2 inhibitor, acts downstream of KRAS. Here we evaluate trametinib as an Id1 inhibitor able to enhance immunotherapy efficacy through PD-L1 overexpression.
Methods
To explore whether MEK1/2 inhibition reduces Id1 expression, human and murine KRAS mutant as well as human KRAS wild-type cell lines were treated with trametinib at different concentrations and time points. A specific shRNA against Id1 was used to compare Id1 silenced cells with cells treated with trametinib. Syngeneic subcutaneous tumors were generated using LLC cells in C57BL6J and Id1 deficient mice treated with PBS or with daily trametinib (0.5 mg/Kg). PD-L1 expression was measured by flow cytometry. Id1 overexpressing and trametinib resistant cell lines were generated to evaluate the role of Id1 in the trametinib signature.
Results
In vitro experiments with NSCLC cell lines treated with trametinib revealed that MEK1/2 inhibition reduces Id1expression. The comparison between cells treated with trametinib and Id1 silenced cells showed the same signature. In vivo experiments did not show significant differences in tumor growth between Id1 knock-out and Id1 wild-type mice treated with trametinib. IHC analysis of tumor samples from these mice showed reduced Id1 levels (p<0.05). Flow cytometry analysis revealed that trametinib increased PD-L1 expression (p<0.001). To assess whether PD-L1 overexpression was Id1-dependant, we generated Id1 overexpressing cells and trametinib resistant cells with unchanged PD-L1 expression. Final data of the therapeutic efficacy of trametinib and anti-PD-1 combination therapy in in vivo models will also be presented.
Conclusions
Pharmacological inhibition of MEK1/2 decreased Id1 expression in vitro and in vivo, replicating a specific shRNA against Id1. PD-L1 upregulation induced by Id1 blockade after trametinib treatment could be used as a novel therapeutic strategy to sensitize NSCLC to PD-1/PD-L1 immunotherapy.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Instituto de Salud Carlos III.
Disclosure
All authors have declared no conflicts of interest.