Inherited Variation in OATP1B1 Is Associated With Treatment Outcome in Acute Myeloid Leukemia

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Abstract

Using broad interrogation of clinically relevant drug absorption, distribution, metabolism, and excretion (ADME) genes on the DMET platform, we identified a genetic variant inSLCO1B1(rs2291075; c.597C>T), encoding the transporter OATP1B1, associated with event-free (P= 0.006, hazard ratio = 1.74) and overall survival (P= 0.012, hazard ratio = 1.85) in children withde novoacute myeloid leukemia (AML). Lack ofSLCO1B1expression in leukemic blasts suggested the association might be due to an inherited rather than a somatic effect. rs2291075 was in strong linkage with known functional variants rs2306283 (c.388A>G) and rs4149056 (c.521T>C). Functional studiesin vitrodetermined that four AML-directed chemotherapeutics (cytarabine, daunorubicin, etoposide, and mitoxantrone) are substrates for OATP1B1 and the mouse ortholog Oatp1b2.In vivopharmacokinetic studies using Oatp1b2-deficient mice further confirmed our results. Collectively, these findings demonstrate an important role for OATP1B1 in the systemic pharmacokinetics of multiple drugs used in the treatment of AML and suggest that inherited variability in host transporter function influences the effectiveness of therapy.

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