APE1 Attenuates ALK Tyrosine Kinase Inhibitors Sensitivity in NPM1-ALK Positive Anaplastic Large Cell Lymphoma

Anaplastic lymphoma kinase (ALK), a tyrosine kinase receptor of the RTK insulin superfamily, was named after its initial identification in anaplastic large cell lymphoma (ALCL). Following a reciprocal chromosomal translocation with nucleophosmin 1 (NPM1), ALK protein is abnormally expressed, promoting the malignant transformation of T cells into a more aggressive lymphoma. The inhibition of ALK activity could therefore benefit ALK+ ALCL patients. Despite the market availability and success of ALK tyrosine kinase inhibitors (TKIs), real-world ALK+ ALCL patients exhibit significant heterogeneity in terms of disease stage at first diagnosis, tumor progression, and responses to medication. This indicates a need for more detailed differentiation of ALK+ ALCL patients in clinical practice. Here, we discovered that apurinic/apyrimidinic endonuclease-reduction/oxidation factor 1 (APE1/REF1), an interacting partner of NPM1, could stabilize NPM1-ALK fusion protein oligomers and enhance ALK tumor-promoting activity and growth, decreasing cell sensitivity to ALK-TKIs. Our results also reveal that disruption of the interaction weakens cell growth and augments the therapeutic efficacy of crizotinib and alectinib, ALK-TKIs, against ALK+ ALCL. Thus, high expression of APE1 indicates a faster growth of ALK+ ALCL; targeting this interaction may potentially achieve improved therapeutic outcomes, providing a reference for more precise treatment of ALK+ ALCL patients in clinical practice.