Pharmacogenetics of tyrosine kinase inhibitors in gastrointestinal stromal tumor and chronic myeloid leukemia

ABSTRACT

Introduction: Gastrointestinal stromal tumors (GIST) and chronic myeloid leukemia (CML) are two tumor types deeply different from each other. Despite the differences, these disorders share treatment with tyrosine kinase inhibitor imatinib. Despite the success of imatinib, the response rates vary among different individuals and pharmacogenetics may play an important role in the final clinical outcome.

Areas covered: In this review, the authors provide an overview of the pharmacogenetic literature analyzing the role of polymorphisms in both GIST and CML treatment efficacy and toxicity.

Expert opinion: So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib have been identified. However, the data are not yet conclusive enough to translate pharmacogenetic tests in clinical practice. In this context, the major obstacles to pharmacogenetic test validation are represented by the small sample size of most studies, ethnicity and population admixture as confounding source, and uncertainty related to genetic variants analyzed. In conclusion, a combination of different theoretical approaches, experimental model systems and statistical methods is clearly needed, in order to appreciate pharmacogenetics applied to clinical practice in the near future.

KEYWORDS:

• Chronic myeloid leukemia
• gastrointestinal stromal tumor
• pharmacogenetics
• polymorphisms
• single nucleotide polymorphism
• tyrosine kinase inhibitors

Article highlights

• Pharmacogenetics allows understanding how patient genotype, including mutations and polymorphisms, may influence clinical efficacy and/or toxicity and the development of resistance to a pharmacological treatment.

• The development of TKIs has dramatically improved the outcomes for GIST and CML patients.

• The use of imatinib, the first KIT inhibitor, has revolutionized to such an extent the GIST therapy, stimulating enormously the research and leading to the development of secondary TKIs as sunitinib and regorafenib.

• To date, four studies have investigated the association between polymorphisms in genes involved in pharmacokinetics of imatinib, mainly transporter genes, and clinical outcome; one study analysed the correlation among polymorphisms on VEGF path and toxicity sunitinib-related.

• The landscape of CML management has changed with the advent of TKIs targeting the BCR-ABL oncoprotein, and now clinicians have access to three first choice drugs, imatinib, nilotinib and dasatinib.

• Several studies have investigated if polymorphisms in genes involved in imatinib pharmacokinetics, including transporters and metabolizing genes, may influence the clinical outcome to imatinib. No studies evaluating the correlation between polymorphisms and other TKIs have been conducting.

• So far, several polymorphisms influencing the pharmacokinetic determinants of imatinib have been identified. However, data are not yet conclusive enough to translate into drug dose adjustment ad personam, and/or predict efficacy/toxicity in the adjuvant and neoadjuvant setting.

• A combination of different theoretical approaches, experimental model systems and statistical methods is clearly needed, in order to appreciate pharmacogenetics applied to clinical practice in the near future.

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Declaration of interests

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.