Abstract
The tumor suppressor gene TP53 is the most frequently mutated gene in cancer. The compound APR‐246 (PRIMA‐1Met/Eprenetapopt) is converted to methylene quinuclidinone (MQ) that targets mutant p53 protein and perturbs cellular antioxidant balance. APR‐246 is currently tested in a phase III clinical trial in myelodysplastic syndrome (MDS). By in vitro, ex vivo, and in vivo models, we show that combined treatment with APR‐246 and inhibitors of efflux pump MRP1/ABCC1 results in synergistic tumor cell death, which is more pronounced in TP53 mutant cells. This is associated with altered cellular thiol status and increased intracellular glutathione‐conjugated MQ (GS‐MQ). Due to the reversibility of MQ conjugation, GS‐MQ forms an intracellular drug reservoir that increases availability of MQ for targeting mutant p53. Our study shows that redox homeostasis is a critical determinant of the response to mutant p53‐targeted cancer therapy.
Highlights
The tumor suppressor p53 is a transcription factor that regulates multiple cellular processes including cell cycle arrest, metabolism, redox homeostasis, and cell death in response to cellular stress (Mello & Attardi, 2018)
We demonstrate that GS-methylene quinuclidinone (MQ) adduct formation is reversible, indicating that GS-MQ could serve as an intracellular drug reservoir to promote mutant p53 reactivation
ABCC1/multidrug resistance-associated protein 1 (MRP1) is one of the genes with the highest correlation to PRIMA-1 resistance in ovarian cancer cells according to data available through the Cancer Dependency Map (DepMap) (Fig EV1A) (Basu et al, 2013; Seashore-Ludlow et al, 2015; Rees et al, 2016) consistent with our NCI database analysis (Bykov et al, 2002a)
Summary
The tumor suppressor p53 is a transcription factor that regulates multiple cellular processes including cell cycle arrest, metabolism, redox homeostasis, and cell death in response to cellular stress (Mello & Attardi, 2018). Mutant p53 may in some settings have gain-of-function (GOF) activities that promote tumor growth (Muller & Vousden, 2014). The mutant p53-targeting compounds PRIMA-1 and APR-246 (PRIMA-1Met/Eprenetapopt) are converted to the active product methylene quinuclidinone (MQ), a Michael acceptor that reacts with thiols (Lambert et al, 2009). Treatment of mutant p53expressing cells with PRIMA-1 or APR-246 results in mutant p53 reactivation and cell death (Bykov et al, 2002b). A clinical phase I/II study has shown that APR-246 is safe and well tolerated (Lehmann et al, 2012). APR-246 is currently undergoing a phase III clinical trial in myelodysplastic syndrome (MDS) and several phase II clinical trials (https://clinicaltrials.gov)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have