What is the relationship between TP53 (tumor protein p53) and selinexor (Xpovio, selinexor)?

From the Guidelines

Selinexor is a viable treatment option for patients with relapsed or refractory multiple myeloma, particularly those with wild-type p53, due to its mechanism of action that blocks exportin-1 and prevents the transport of tumor suppressor proteins like p53 out of the cell nucleus, as demonstrated in the phase 2 STORM study 1. The relationship between p53 and selinexor is crucial in cancer treatment, as selinexor works by blocking exportin-1 (XPO1), preventing the transport of tumor suppressor proteins like p53 out of the cell nucleus. This is significant because p53 is a critical tumor suppressor that becomes dysfunctional in many cancers. By keeping p53 in the nucleus where it can function properly, selinexor helps restore its tumor-suppressing activity. Some key points to consider when using selinexor include:

• Selinexor is FDA-approved for multiple myeloma (typically at 80-100mg doses twice weekly) and diffuse large B-cell lymphoma (60mg twice weekly) 1.
• Common side effects include nausea, fatigue, decreased appetite, weight loss, thrombocytopenia, and hyponatremia.
• Supportive care with antiemetics, appetite stimulants, and close monitoring of blood counts and electrolytes is essential during treatment.
• The mechanism of action through p53 retention makes selinexor particularly interesting for cancers with wild-type p53 that is being inappropriately exported from the nucleus, though it has activity even in some p53-mutated cancers through effects on other tumor suppressor proteins. In the context of multiple myeloma, selinexor has shown efficacy in patients who have received multiple prior therapies and are refractory to IMiDs, proteasome inhibitors, and the CD38 antibody, as demonstrated in the phase 2 STORM study 1. The use of selinexor in combination with dexamethasone is a recommended option for patients with relapsed or refractory multiple myeloma who have received at least 4 prior therapies and whose disease is refractory to at least 2 proteasome inhibitors, at least 2 IMiD agents, and an anti-CD38 monoclonal antibody 1.

From the Research

Selinexor and p53 Interaction

• Selinexor has been shown to induce p53 nuclear accumulation, allowing p53 to function as a tumor suppressor 2.
• The combination of selinexor and azacitidine synergistically inhibits myelodysplastic syndrome cell proliferation and promotes apoptosis, with enhanced p53 accumulation in the nucleus 2.
• Selinexor induces cytotoxic effects in neuroblastoma cells through the nuclear accumulation of p53 and global activation of apoptosis pathways 3.

p53 Signaling Pathway

• p53 is a well-studied tumor suppressor, mutated or deleted in half of all cancers, and its signaling pathway is disrupted in the other half 4.
• Targeting the p53 signaling pathway has attracted great interest in drug development, but designing therapeutics has been challenging 4.
• Combining selinexor with other agents, such as alisertib, may target the p53 pathway and increase p53-mediated cytotoxicity in high-risk neuroblastoma 3.

Selinexor Mechanism of Action

• Selinexor is a nuclear export protein inhibitor that blocks cell proliferation and induces apoptosis in various cancer cell lines 5, 2.
• Selinexor causes thrombocytopenia by blocking thrombopoietin signaling and differentiation of stem cells into megakaryocytes 5.
• The mechanism of selinexor-induced thrombocytopenia is reversible with the administration of thrombopoietin agonists in the absence of selinexor 5.