Novel Benefits and Consequences Associated with Altered Transporter Activity During Cancer Treatment

Solute carriers include numerous uptake transporters that serve as major regulators of drug absorption, disposition, and clearance. Indeed, drug interactions or genetic variation that alter solute carrier activity can impact patient outcome by modifying drug pharmacokinetics to yield changes in efficacy or toxicity. Our group has recently shown that many tyrosine kinase inhibitors (TKIs), which are a class of small molecule drugs used to treat a variety of diseases that include cancer, rheumatoid arthritis, pulmonary fibrosis, and macular degeneration, can inhibit the function of a variety of uptake transporters through a novel non-competitive mechanism. For example, numerous reports of clinical drug interactions among TKIs and substrates of the hepatic solute carrier known as the organic anion transporting polypeptide OATP1B1 transporter have been reported, where systemic concentration of OATP1B1 substrates, along with the severity of their toxicity, are elevated. This presentation will outline our efforts in clarifying how TKIs that inhibit the tyrosine kinase known as LYN will alter OATP1B1 activity resulting in diminished hepatic uptake and elevated systemic concentrations of various substrates, ultimately leading to potentially life-threatening toxic risks. Overall, these findings serve to better predict dangerous drug interactions or guide drug development in avoiding particular off target kinases. Moreover, this session will serve to highlight the potential of TKIs to similarly impact the activity of other solute carriers through altered kinase activity, as well as outline possible clinical strategies that can be developed to improve patient outcome with this knowledge.

Learning Objectives:

• Identify risk of Tyrosine Kinase Inhibitor Drug Interactions with OATP1B substrates
• Describe the regulation of solute carriers by tyrosine kinase activity/phosphorylation and its sensitivity to tyrosine kinase inhibitors
• Interpret the benefit of using tyrosine kinase inhibitors to manipulate solute carriers involved in platinum toxicity