Only 21 of 48 p53 Mutations May Respond to ATO Combination Therapy

A study found that only 21 of 48 p53 mutations may respond to combination therapy with arsenic trioxide (ATO) and decitabine.

Researchers from Shanghai Jiao Tong University in China, including Lu Min, Wu Jiale and Professor Zhang Sujiang, published the findings in the international journal Science Translational Medicine on the 12th (local time).

Acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) with p53 mutations are often resistant to standard treatments, including chemotherapy and hematopoietic stem cell transplantation.

The researchers focused on the ability of ATO to restore the function of p53 with structural mutations. ATO is approved to treat acute promyelocytic leukemia (M3 subtype).

The researchers found that mutant p53 whose function had been restored by ATO directly activates interferon regulatory factor 7 (IRF7), enhancing the interferon response induced by decitabine.

Decitabine induced serine 20 phosphorylation of p53 and blocked MDM2, which suppresses p53, further increasing the activity of mutant p53 restored by ATO.

The researchers administered ATO and decitabine in combination in the first human clinical trial (PANDA-T0, NCT03855371) involving 5 patients with p53-mutated AML or MDS.

The treatment resulted in manageable adverse events, and 4 of the 5 patients achieved complete remission at the bone marrow level. This was associated with p53 activation and the interferon response.

The researchers identified 48 distinct p53 missense mutations in samples from 103 patients with p53 mutations stored in the sample bank at Ruijin Hospital in Shanghai.

Of these, 21 mutations were classified as capable of activating p53 and the interferon response with the combination therapy. The researchers determined that these 21 mutations were suitable for combination treatment with ATO and decitabine.

The researchers said the study provides an alternative treatment approach for patients with p53-mutated AML or MDS and a proof-of-concept framework for distinguishing p53 mutations and applying targeted treatment.