Via Research Recognition Day 2024 VCOM-Carolinas

Biomedical Studies

Current Progress on the Influence Human Genetics Has on the Efficacy of Tyrosine Kinase Inhibitors Used to Treat Chronic Myeloid Leukemia Tara Prakash, OMS-III and Steven A. Enkemann, Ph.D. Edward Via College of Osteopathic Medicine, Dept. of Cell Biology and Physiology, Spartanburg, South Carolina

Results

Conclusions

Abstract Background

Conclusions

Liver Enzymes • Liver enzymes are a natural pharmacogenetic consideration when looking at how human variation can affect drug efficacy • Liver enzyme interactions are summarized on Table 1 • Human variation in liver metabolism may not be particularly relevant in imatinib, nilotinib, and bosutinib efficacy as these drugs are slowly metabolized and the majority of their administered dose is excreted unchanged • Dasatinib may be the exception to this rule due to its short half-life and the fact that only the minority of the administered dose is excreted unchanged. Thus, its interaction with liver enzymes should be further investigated. Transporters • Efflux transporters have been a major focus in the study of TKI metabolism • Known data regarding which transporters interact with which drugs is summarized in Table 2 • Existing studies do not account for the ubiquity of the expression of these transporters, ability of many tumors to overexpress proteins, or the fact that multiple transporters could be acting in concert • The above factors should be isolated in future research • Lesser-known transporters may be involved and are an important avenue for future research

• Chronic myeloid leukemia (CML) develops when hematopoietic stem cells acquire a reciprocal translocation between chromosomes 9 and 22 creating a fusion between the breakpoint cluster region (BCR) and the Abelson (ABL) gene [2]

Results Nilotinib Dasatinib Bosutinib ͵ Ͷ —„•–”ƒ–‡ȗ —„•–”ƒ–‡ȗ —„•–”ƒ–‡ȗ —„•–”ƒ–‡ȗ ͵ ͷ —‹„•Š– ‹”„ƒ‹––‡‘ȗ”ǡ ‹Š‹„‹–‘” ʹ ͸ ‹†— ‡” ʹ ͺ •—„•–”ƒ–‡ ‹ ‹ Š†‹ „— ‹ –‡‘””ǡ ʹ ͻ ‘ ‹–‡”ƒ –‹‘ ‹Š‹„‹–‘”ǡ ‹†— ‡” ʹ ʹ ͳ ͸ ͻ ‘ ‹–‡”ƒ –‹‘ ‘ ‹–‡”ƒ –‹‘ ‹Š‹„‹–‘” ʹ ͺ •—„•–”ƒ–‡ ‹Š‹„‹–‘” ͳ ͳ ‹Š‹„‹–‘” ‹Š‹„‹–‘” ƒŽˆǦŽ‹ˆ‡ ͳͺǦͶͲ Š”• ͳ͸ Š”• ͵Ǧͷ Š”• ͳͺǦͶͲ Š”• Transporter Imatinib Nilotinib Dasatinib Bosutinib ABCB1 —„•–”ƒ–‡ —„•–”ƒ–‡ —„•–”ƒ–‡ —„•–”ƒ–‡ ABCG2 Š‹„‹–‘” —„•–”ƒ–‡ —„•–”ƒ–‡ ‘ ‹–‡”ƒ –‹‘ ABCC4 —„•–”ƒ–‡ ABCC6 —„•–”ƒ–‡ OCT-1 —„•–”ƒ–‡ ‘ ‹–‡”ƒ –‹‘ ‘ ‹–‡”ƒ –‹‘ ‘ ‹–‡”ƒ –‹‘ OCT-2 ‘ ‹–‡”ƒ –‹‘ ‘ ‹–‡”ƒ –‹‘ SLCO1A2 —„•–”ƒ–‡ Table 1 . TKI interactions with liver enzymes. * = primary interaction. . Table 2 . TKI interactions with transporter proteins. Substrate indicates the TKI is a substrate for the protein, “no interaction” indicates that the TKI has been explicitly studied and research has not found there to be any interaction, an empty space signifies that the transporter has not been explicitly studied yet. . Liver Enzymes Imatinib

https://www.hybrigenics.com/contents/inecalcitol-2/chronic-myeloid-leukemia

• Tyrosine kinase inhibitors (TKIs) used in CML serve as distinguished examples of targeted therapy due to their high efficacy [2]

Introduction

• Imatinib, the first TKI to achieve FDA approval, has not been the panacea initially expected for CML [1,2] • Due to resistance mechanisms and other tumor characteristics, second generation TKIs are currently available to treat CML[14] • This review aims to discuss genetic factors that may influence the efficacy of four FDA approved TKIs used in the treatment of CML -- imatinib, nilotinib, dasatinib, and bosutinib • The objective is to establish criteria whereby one drug would be preferred over the others, with a focus on CYP enztmes and transporters since these factors have shown to affect the metabolism of several other drugs

.

References

Methods

A literature search was performed to review the history of TKIs in CML treatment, mechanisms of action of the drugs, and their metabolism. Any enzymes involved in TKI activity or metabolism were further investigated for human variation that might alter their activity and thus influence the efficacy of TKIs.

We would like to acknowledge the helpful efforts of the Library Staff at the Carolinas Campus who helped procure difficult to find manuscripts.

6

2024 Research Recognition Day