Resistance to tyrosine kinase inhibitors: Calling on extra forces

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Abstract

Over the past 5 years, small molecule tyrosine kinase inhibitors have been successfully introduced as new cancer therapeutics. The pioneering work with the ABL inhibitor imatinib (Glivec, Gleevec) was rapidly extended to other types of leukemias as well as solid tumors, which stimulated the development of a variety of new tyrosine kinase inhibitors. Unfortunately, oncogenic tyrosine kinases seem to have little problem to develop resistance to these inhibitors, and there is good evidence that this is not limited to imatinib, but also occurs with other inhibitors, such as FLT3 and EGFR inhibitors. Based on studies with imatinib, mutation and amplification of the target kinase seem to be the most important mechanisms for the development of resistance, but these mechanisms alone cannot explain all cases of resistance. A better understanding of the resistance mechanisms will be required to design improved treatment strategies in the future. In this review, we summarize the current insights in the different mechanisms of resistance to small molecule tyrosine kinase inhibitors, and discuss future improvements that might limit or even overcome resistance.

Introduction

Protein tyrosine kinases (PTKs) constitute an important family of signaling proteins that are involved in a variety of cellular processes, including proliferation, cell migration, differentiation, and survival. Most of the PTKs are transmembrane receptors that are activated upon ligand binding, while the remaining PTKs are cytosolic proteins that are activated downstream of transmembrane receptors or by other signaling proteins. Activation of PTKs by extracellular or intracellular stimuli results in the phosphorylation of a panel of intracellular signaling proteins, which link the PTKs with other pathways such as the PI3K pathway, the RAS/MAPK pathway, STATs, PLCγ, etc. The human genome contains 90 genes that encode proteins with putative tyrosine kinase activity (Manning et al., 2002). Of these, already 20 have been shown to be implicated in the pathogenesis of hematological malignancies or solid tumors. Important examples include the BCR-ABL1 fusion, implicated in the pathogenesis of chronic myeloid leukemia (CML) and B-cell acute lymphoblastic leukemia (B-ALL) (Ren, 2005), the NUP214-ABL1 fusion in T-cell acute lymphoblastic leukemia (T-ALL) (Graux et al., 2004, De Keersmaecker et al., 2005), FLT3 internal tandem duplications and point mutations in acute myeloid leukemia (AML) (Gilliland and Griffin, 2002), FIP1L1-PDGFRα fusion in chronic eosinophilic leukemia (CEL) (Cools et al., 2003a), variant PDGFRβ fusions in chronic myelomonocytic leukemia (CMML) (Apperley et al., 2002, Levine et al., 2005b), variant ALK fusions in anaplastic large cell lymphoma (ALCL) (Cools et al., 2002), EGFR mutations in non-small cell lung cancer (Paez et al., 2004, Lynch et al., 2004), KIT mutations in gastrointestinal stromal tumors (GIST) and systemic mast cell disease (SMCD) (Heinrich et al., 2002), and most recently, mutation of JAK2 in myeloproliferative diseases (Baxter et al., 2005, Levine et al., 2005a).

Numerous studies have suggested a critical role for oncogenic PTKs in the proliferation and survival of cancer cells (Cools et al., 2004b, Kelly et al., 2002), supplying the rationale and incentive for investigating these proteins as drug targets. In a landmark paper of 1996, Brian Druker described the effect of a small molecule kinase inhibitor, imatinib mesylate, on the growth and survival of BCR-ABL1 positive cell lines (Druker et al., 1996). Further studies on the therapeutic application of imatinib and clinical trials finally led to the approval of this drug for the treatment of CML. Imatinib mesylate (STI571, Glivec, Gleevec; Novartis) is a specific inhibitor of ABL1, ABL2 (ARG), KIT, PDGFRα, and PDGFRβ (Capdeville et al., 2002). Imatinib has good specificity, can be orally administered, is well tolerated with only minor toxicities, and is very effective in the treatment of BCR-ABL1 positive CML in chronic phase, with 95% of patients achieving complete hematological remission. After its approval for the treatment of CML patients, the efficacy of imatinib for the treatment of other leukemias as well as solid tumors has been explored. Imatinib is now used for the treatment of FIP1L1-PDGFRα positive CEL (Cools et al., 2003a), CMML with rearrangements of PDGFRβ (Apperley et al., 2002), and GISTs with KIT or PDGFRα mutations (Demetri et al., 2002, Heinrich et al., 2003b).

Based on the success of imatinib, several small molecule tyrosine kinase inhibitors with activity against FLT3 and EGFR have been developed for clinical use. FLT3 inhibitors were shown to be efficient to inhibit the growth of FLT3 mutation positive cell lines, and to treat FLT3 mutation-mediated hematological disease in mice (Kelly et al., 2002, Weisberg et al., 2002, Levis et al., 2002). In addition, the first clinical trials with FLT3 inhibitors for the treatment of AML show promising results (O’Farrell et al., 2003, Smith et al., 2004, Stone et al., 2005). Similarly, the EGFR inhibitor gefitinib was shown to be effective in the treatment of NSCLC expressing mutated EGFR (Lynch et al., 2004, Paez et al., 2004).

A general drawback with the current small molecule tyrosine kinase inhibitors is the relative ease by which kinases can develop resistance to these drugs when applied as single agents. Imatinib induces complete hematological remission in the majority of patients with chronic phase CML, CMML and CEL, but is less effective for the treatment of more advanced cancers, such as CML in blast crisis, B-ALL and GISTs (Druker et al., 2001a, Druker et al., 2001b, Demetri et al., 2002, Cools et al., 2003a, Apperley et al., 2002). In addition, resistance develops frequently and rapidly in these more advanced tumors (Hofmann et al., 2004, Debiec-Rychter et al., 2005). Resistance is less of a problem in chronic leukemias, but resistance could become more important for these patients too as they are followed over longer time periods, especially since imatinib is unable to eradicate all BCR-ABL1 positive cells in most patients. Several mechanisms have been described that can cause resistance to small molecule inhibitors, and detailed understanding of these may allow the development of better treatment strategies to overcome or prevent the development of resistance.

Section snippets

Mutation of the target kinase

Imatinib, as well as most other small molecule kinase inhibitors, is an ATP competitor; its interference with kinase activity is strictly dependent on ATP availability (Capdeville et al., 2002). Both ATP and the inhibitors need to fit within the ATP-binding pocket of the kinase domain, their binding being stabilized by interactions with specific amino acids in the binding site (Schindler et al., 2000). As a consequence, point mutations that result in changes of critical amino acids in contact

Overcoming resistance using combinations of tyrosine kinase inhibitors

Since the identification of the first resistance mutations in BCR-ABL1, the hunt for new ABL inhibitors with activity against these imatinib-resistant forms commenced. Several new compounds were identified, but unfavorable pharmacokinetic profiles precluded their clinical development. Nevertheless, through screening and rational drug design, some second generation ABL inhibitors with the required characteristics were selected and are now being evaluated in clinical trials.

AMN107 is a structural

Future perspectives

Now that the first years of imatinib trials have shown good results in leukemia patients in the chronic phase, there is hope that we will be able to prevent these patients from future progression to blast crisis by starting treatment early on. On the other hand, we still have only relatively short follow up of leukemia patients in the chronic phase, and there is definitively a possibility that resistance could develop after several years of imatinib treatment. It is in this context that we will

Acknowledgments

Jan Cools and Chantal Maertens are postdoctoral researchers of the FWO-Vlaanderen. Our work is supported by the FWO-Vlaanderen, the Belgian Federation against Cancer (BFK), and the European Hematology Association (EHA). We thank Kim De Keersmaecker for critical reading of the manuscript.

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