Prolonged Idasanutlin (RG7388) Treatment Leads to the Generation of p53-Mutated Cells

Protein p53 plays a critical role in protecting against carcinogenic events by inducing cell cycle arrest and initiating DNA repair upon DNA damage. Many cancers inactivate p53 either through mutations or deletions of the TP53 gene or by enhancing negative regulation of its activity.

Overexpression of MDM2 is a common mechanism in p53 wild-type cancers to keep p53 inactive. Inhibition of MDM2 with specific antagonists has shown promising anticancer potential in vitro and is now being evaluated in clinical trials.

However, prolonged treatment of p53 wild-type cells with MDM2 antagonists can lead to secondary resistance—a phenomenon first observed with Nutlin-3a and later with other small molecules.

In this study, we demonstrate that secondary resistance also occurs with idasanutlin (RG7388, RO5503781), the only MDM2 antagonist that has advanced from phase II to phase III clinical trials so far.

Idasanutlin strongly activates p53, as evidenced by the induction of p21 expression and potent cell cycle arrest in all three cell lines tested (MCF-7, U-2 OS, and SJSA-1). Notably, apoptosis was induced only in SJSA-1 cells, while MCF-7 and U-2 OS cells resumed proliferation upon removal of idasanutlin.

Moreover, U-2 OS cells treated with idasanutlin could be cultured long-term in the presence of the drug, and this prolonged exposure led to the de novo generation of p53-mutated resistant cell populations, as confirmed by studies using monoclonal U-2 OS subpopulations.

Thus, although idasanutlin exhibits improved activity compared to its precursor, it still suffers from limited elimination of cancer cells and the emergence of p53-mutated, drug-resistant subpopulations.