EACR25-2115

Idasanutlin in combination with PD-1 blockade - synergy or antagonism?

L. Skalniak¹, A. Nieznanska¹, M. Statkiewicz², Z. Sandowska-Markiewicz², K. Unrug-Bielawska², A. Majewska¹, M. Mikula², J. Ostrowski², T. Holak¹

¹Jagiellonian University, Department of Organic Chemistry, Faculty of Chemistry, Krakow, Poland
²Maria Sklodowska-Curie National Research Institute of Oncology, Department of Genetics, Warsaw, Poland

Introduction:

The blockade of the PD-1/PD-L1 immune checkpoint has become a well-recognized strategy in the treatment of cancer. Due to the limited response in a considerable proportion of patients, diverse drug combinations have been proposed, including small-molecule antagonists of MDM2, such as idasanutlin. In p53 wild-type cancer cells, MDM2 antagonists lead to forced activation of the p53 protein, causing potent cell cycle arrest but only limited cancer cell apoptosis. A combination of PD-1 blockade and p53 activation has been proposed to be beneficial for both treatments. This study aims at a verification of this hypothesis in vitro and in vivo.

Material and method:

MDM2 antagonist idasanutlin was tested against mouse and human cancer cell lines in terms of p53-induced protein expression, cell cycle blockade, cell survival decrease, activation of apoptosis, and induction of PD-L1 expression. A syngeneic CT26/BALB/c mouse model was used to assess the therapeutic effects of the combination of PD-1 blockade and p53 activation in vivo.

Result and discussion:

Idasanutlin effectively reactivates p53 in p53-wt human cancer cell lines, leading to potent cell cycle arrest but only limited apoptosis. Similar results are observed for mouse cell lines but at considerably higher concentrations. p53-wt/p53-mut selectivity observed for human cell lines is retained in mouse cell lines. Idasanutlin seemingly increases the expression of PD-L1, but the introduction of a new in vitro model questions this notion. The combination of PD-1 blockade with low doses of idasanutlin in vivo leads to a positive interaction of both treatments, while high doses of MDM2 antagonist cause deleterious effects to this immunotherapy approach.

Conclusion:

The results confirm the limited ability of MDM2 antagonists alone to eliminate cancer cells. The in vivo study underscores important aspects of combining the two therapeutic approaches, which can bring both completing and opposing effects. This research was supported by the Preludium grant 2019/35/N/NZ5/03991 and Sonata Bis grant 2021/42/E/NZ7/00422 from the National Science Centre, Poland.