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Activation of Tyrosine Kinases in Cancer

Duke University Medical Center, Division of Hematology/Oncology, Durham, North Carolina, USA

Correspondence: Jeffrey Crawford, M.D., Duke University Medical Center, Box 3198, Morris Building, Room 25178, Durham, North Carolina 27710, USA. Telephone: 919-684-5195; Fax: 919-681-5864; e-mail: crawf006{at}mc.duke.edu

	LEARNING OBJECTIVES

Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 
After completing this course, the reader will be able to:

1. Identify the advantages of small molecule inhibitors.
   
2. Explain the significant role that tyrosine kinase plays in signal transduction.
   
3. Describe the tyrosine kinase inhibitors clinical data.
   

	ABSTRACT

Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 
Receptor and nonreceptor tyrosine kinases (TKs) have emerged as clinically useful drug target molecules for treating certain types of cancer. Epidermal growth factor receptor (EGFR)-TK is a transmembrane receptor TK that is overexpressed or aberrantly activated in the most common solid tumors, including non-small cell lung cancer and cancers of the breast, prostate, and colon. Activation of the EGFR-TK enzyme results in autophosphorylation, which drives signal transduction pathways leading to tumor growth and malignant progression. Randomized clinical trials of the EGFR-TK inhibitor gefitinib have demonstrated clinical benefits in patients with advanced non-small cell lung cancer whose disease had previously progressed on platinum- and docetaxel-based chemotherapy regimens. Bcr-Abl is a constitutively activated nonreceptor TK enzyme found in the cytoplasm of Philadelphia chromosome-positive leukemia cells. STI571 (imatinib mesylate) inhibits the Bcr-Abl TK, blocks the growth of these leukemia cells, and induces apoptosis. STI571 also inhibits other TKs, including the receptor TK c-kit, which is expressed in gastrointestinal stromal tumors. As TK inhibitors become available for clinical use, new challenges include predicting which patients are most likely to respond to these targeted TK inhibitors. Additional clinical trials are needed to develop the full potential of receptor and nonreceptor TK inhibitors for cancer treatment.

Key Words. Tyrosine kinase • Cancer • Epidermal growth factor receptor-tyrosine kinase • Bcr-Abl • Gefitinib • STI571

	INTRODUCTION

Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 
The clinical development of targeted tyrosine kinase (TK) inhibitors for cancer treatment represents a breakthrough in the understanding of the molecular mechanisms of disease, and a challenge in reevaluating existing intervention strategies. Small-molecule TK inhibitors, such as STI571 (imatinib mesylate, Gleevec^TM; Novartis Pharmaceuticals Corporation; East Hanover, NJ), gefitinib (Iressa^®; AstraZeneca Pharmaceuticals LP; Wilmington, DE), and OSI-774 (erlotinib, Tarceva^TM; OSI Pharmaceuticals; Melville, NY/Genentech; South San Francisco, CA), are different from antibody-based therapies in that they enter tumor cells and directly interfere with TK enzymes that are aberrantly activated in tumor cells and are critical to the growth of the tumor. Oral bioavailability and good tolerability profiles also distinguish these agents from conventional cytotoxic chemotherapies. It is important to understand this new approach to cancer treatment in order to identify how it best fits with current treatment practices and to maximize its potential.

	TKS AS TARGETS FOR ANTITUMOR THERAPY

Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 
TKs are enzymes that transfer -phosphate groups from ATP to the hydroxyl group of tyrosine residues on signal transduction molecules [1]. Phosphorylation of signal transduction molecules is a major activating event that leads to dramatic changes in tumor growth. Some TKs, such as epidermal growth factor receptor (EGFR)-TK, can autophosphorylate when activated, as well as phosphorylating other signaling molecules [2]. The resulting phosphotyrosine residues in the EGFR-TK cytoplasmic domain serve to further activate the TK activity of the receptor and to act as docking sites for cytoplasmic signal transduction molecules containing Src homology or phosphotyrosine binding motifs [1]. Tyrosine kinases play a central role in signal transduction, acting as relay points for a complex network of interdependent signaling molecules that ultimately affect gene transcription within the nucleus. Strict regulation of TK activity controls the most fundamental processes of cells, such as the cell cycle, proliferation, differentiation, motility, and cell death or survival [3, 4]. In tumor cells, it is common that key TKs are no longer adequately controlled, and excessive phosphorylation sustains signal transduction pathways in an activated state.

Approximately 90 TKs have been identified, 58 of which are the transmembrane receptor type and 32 the cytoplasmic nonreceptor type [5]. TK receptors transduce signals from both outside and inside the cell and function as relay points for signaling pathways inside the cell. The nonreceptor TKs are found in the cytoplasm; they lack a transmembrane segment and generally function downstream of the receptor TKs. The Bcr-Abl fusion protein and c-Src are examples of nonreceptor TKs that transduce signals inside the cell [5]. Many of both types of TKs are regularly found to be mutated or expressed at high levels in human malignancies [5, 6]. In addition, the ability to transform normal cells or affect tumor cell processes in vitro has been reported for many different TKs. However, clinical agents to inhibit the activity of these molecules have been developed for only a few of these TKs. Examples of clinically targeted transmembrane receptor TKs include the EGFR, the closely related HER-2 (ErbB-2/Neu), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor (VEGF) receptor, and c-kit/stem cell factor receptor [5, 6]. These new targeted therapies are designed to take advantage of the molecular differences specific to tumor cells compared with normal tissues. The goal is to achieve tumor responses with better safety profiles than those associated with cytotoxic chemotherapies.

	EGFR-TK IN CANCER

Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 
Abnormally elevated EGFR-TK activity is associated with the most common human solid tumors, including non-small cell lung cancer (NSCLC), colorectal adenocarcinoma, glioblastoma, squamous cell carcinoma of the head and neck, and gastric, pancreatic, breast, ovarian, cervical, and prostate cancers (Table 1) [4, 7]. From precancerous lesions to malignant tumors, elevated EGFR-TK activity has been detected at all stages of tumor progression [8, 9]. Oncogenic activation of EGFR-TK can occur by multiple mechanisms: excess ligand expression or high expression of EGFR, activating mutation, failure of inactivation mechanisms, or transactivation through receptor dimerization [3, 10, 11]. There are four members of the EGFR family of receptor TKs including ErbB-1 (EGFR), ErbB-2 (HER-2), ErbB-3, and ErbB-4. Ligand binding induces receptor homodimerization or heterodimerization. While ErbB-2 is the preferred binding partner for all other ErbB family members, the actual dimers formed follow a hierarchy of likely binding partners, which is dictated by various factors including the ligand (EGF, NRG-1, BTC) and cell type [12, 13]. Homodimers of ErbB-3 are the only known inactive dimer combination, due to impaired kinase activity. However, heterodimers containing ErbB-3 are able to activate intracellular signaling. The various dimer combinations allow for both signal amplification and diversity. Each EGFR family member is able to recruit a variety of specific signaling molecules that bind to specific phosphotyrosine residues in the intracellular portion of the receptor [2]. Dimerization partners may not only affect the activation of specific signaling pathways but may also affect responses to various ErbB family inhibitors. For example, it is possible that combining inhibitors of EGFR and ErbB-2/HER-2 may synergistically inhibit the growth of some tumor types and reduce resistance. Alternatively, certain binding combinations may reduce the efficacy of some inhibitors if the binding partner is able to robustly activate signaling pathways independently.

View larger version (38K): [in this window] [in a new window]   Figure 1. Signal transduction through EGFR-TK. Ligand binding induces receptor dimerization and autophosphorylation, creating docking sites for adaptor molecules and leading to the activation of downstream effector molecules. A variety of signaling pathways results in pleiotropic effects, including cell proliferation, control of the cell cycle, regulation of apoptosis and survival, and alterations in cell migration and invasiveness [3, 14, 16, 17].

Based on the distribution and role of the EGFR-TK target molecule in human tumors, EGFR-TK inhibitors, such as gefitinib and OSI-774, have the potential to inhibit other common solid tumors in addition to lung cancer, including colon, breast, prostate, cervical and ovarian cancers, squamous cell carcinomas of the head and neck, melanomas, and glioblastomas [35]. This potential is being explored in clinical trials in many common solid tumor types and across all stages of neoplastic progression. Additional studies are ongoing to evaluate EGFR-TK inhibitors as monotherapy or in combination with chemotherapy or radiation therapy.

	BCR-ABL TK: ROLE IN CANCER AND EFFECTS OF TK INHIBITION

Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 
An example of a nonreceptor TK with clinical relevance is Bcr-Abl. It is a fusion protein created by the t(9;22) chromosomal translocation, which generates the distinctive Philadelphia (Ph) chromosome found in some forms of leukemia, including most cases of chronic myelogenous leukemia (CML) and many cases of adult acute lymphoblastic leukemia (ALL) [5]. This translocation juxtaposes the c-abl nonreceptor TK gene on chromosome 9 with a breakpoint cluster region (bcr) gene on chromosome 22. The resulting fusion protein, Bcr-Abl, is a constitutively activated form of the Abl TK that drives uncontrolled growth of Ph⁺ cells. Whereas Abl can translocate to the nucleus, in which it has a role in DNA-damage-induced apoptosis, Bcr-Abl is retained in the cytoplasm in association with the cytoskeleton, where its lack of proapoptotic activity contributes to its oncogenic properties [5, 36].

The 2-phenylaminopyrimidine STI571 is a small-molecule TK inhibitor for the treatment of CML. It inhibits c-Abl and Bcr-Abl, blocking the growth of Bcr-Abl-transformed leukemic cells and inducing apoptosis (Fig. 2) [37–39]. Drug-related adverse effects include nausea, vomiting, myalgias, edema, diarrhea, and, less commonly, anemia, thrombocytopenia, neutropenia, and myelosuppression [40, 41]. In at least the initial stages of treatment, STI571 has been very effective in inhibiting progression of CML and Ph⁺ adult ALL [40, 41]. The ability of this Bcr-Abl inhibitor to act alone is evidence that, in the early stages of disease, this TK is the sole or principal driver of growth in leukemic cells. However, most patients in the advanced stages of disease relapse with STI571-resistant tumor cell variants [42]. CML has a long initial chronic phase, which lasts an average of 3 to 4 years, followed by an accelerated blast phase during which additional mutations accumulate [38, 41]. In a phase I study of patients in blast crisis, 55% of CML patients and 70% of ALL patients initially responded to STI571, but 70% of the first responding group and 100% of the second group relapsed within 6 months [43]. By contrast, patients treated in the earlier, chronic phase of the disease developed drug resistance only rarely and often demonstrated prolonged remissions [42]. These findings suggest that, in early CML, the t(9;22) translocation may be the only genetic alteration responsible for cancer growth. Thus, STI571 is highly effective for early-stage disease. At later stages of the disease, however, other mutations may arise that bypass the inhibition of Bcr-Abl TK, and the control of leukemic progression is less effective.

View larger version (19K): [in this window] [in a new window]   Figure 2. Inhibition of Bcr-Abl by STI571. The Bcr-Abl TK is a fusion protein that is constitutively activated, resulting in inappropriate phosphorylation and activation of downstream signaling and effector molecules. STI571 occupies the ATP binding pocket of the Bcr-Abl TK and, thus, blocks the ability of the enzyme to transfer phosphates from ATP to substrate molecules [38, 39]. Adapted with permission from O’Dwyer and Druker [38].

	POTENTIAL FOR TK-TARGETED THERAPIES ACROSS TUMOR TYPES AND STAGES

Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 
Of the TKs known to drive growth and progression of tumor cells, some (e.g., Bcr-Abl) are restricted to specific types of cancer, whereas others (e.g., EGFR-TK) have transforming capacity in most common types of solid tumors and across tumor stages. In contrast to the situation in CML, in which one gene mutation drives cancer progression, most solid tumors are thought to be the result of several genetic alterations [43]. In this respect, the EGFR may not be the only molecule driving tumor growth. While many common solid tumors may express EGFR, these tumors may result from multiple genetic changes leading to the expression of additional receptor and nonreceptor TKs that play roles in tumor growth. For example, while a tumor expresses EGFR, treatment with an EGFR-TK inhibitor may not necessarily inhibit tumor growth since mutations in other molecules may lead to the activation of several EGFR-dependent and EGFR-independent signaling pathways and subsequent tumor growth. A tumor may express additional TKs, such as Ras or PTEN, that are overexpressed or genetically mutated and are capable of activating downstream signaling. There may not, therefore, be a direct or straightforward correlation between EGFR expression and tumor response. However, as TK activity plays a key role in so many tumorigenic processes, from increased proliferation, invasion, angiogenesis, and metastasis to decreased apoptosis, inhibiting TK activity is likely to have an antitumor effect across the spectrum of disease stages in solid tumors. More research is needed to evaluate the contributions of other TKs and downstream effector molecules to tumor cell growth. In addition, future studies will investigate combinations of targeted agents designed to inhibit multiple mechanisms of tumor growth.

The inhibition of Bcr-Abl TK blocks the progression of a large percentage of Ph⁺ tumors. However, the incidences of Ph⁺ CML and adult ALL are very low. Inhibition of EGFR-TK activity has the potential to benefit a much larger number of cancer patients. For example, it is estimated that 171,900 individuals will be diagnosed with lung cancer in the U.S. in 2003, with NSCLC as the histologic diagnosis in more than 80% of those patients [52]. Most cases of NSCLC are locally advanced or metastatic at initial presentation [53]. Based on the results of the IDEAL-1 and IDEAL-2 trials, many patients with advanced NSCLC could potentially benefit from gefitinib monotherapy. In addition, EGFR-TK is expressed in large numbers in the most common solid tumors. Whereas STI571 may be useful for different tumor types by inhibiting multiple TKs, EGFR-TK inhibitors may have broad applicability in cancer therapy due to the expression and activation of the EGFR-TK target molecule across solid tumor types.

Although it is known that SCLC cell lines and tumor tissue express c-kit, it is unclear what the therapeutic role of STI571 might be in this disease. In vitro studies showed that STI571 inhibits the growth of SCLC cell lines [46]. A phase I clinical trial of standard cisplatin/etoposide with daily STI571 for newly diagnosed SCLC is testing the hypothesis that STI571 (by inhibition of proliferation, induction of apoptosis, and promotion of drug delivery) will enhance the cytotoxic effect of chemotherapy. Another study investigated the cytotoxic effects of STI571 in combination with commonly used antileukemic agents in several Ph⁺ leukemia cell lines. Different combinations of drugs were variously additive, antagonistic, or synergistic in some or all of the cell lines. Interestingly, simultaneous exposure to STI571 and vincristine (a vinca alkaloid) produced synergistic effects in all four cell lines, suggesting that this drug combination might be active against CML in lymphoid crisis and Ph⁺ ALL [54]. The reasoning behind this observation was that mitotic inhibitors, such as vinca alkaloids and taxanes, have been shown to induce phosphorylation of Bcl-2 family proteins, including Bcl-2 and Bcl-x, which is accompanied by loss of function and apoptosis. Oetzel et al. reported that STI571 induced apoptosis in bcr-abl-transfected cell lines by downregulating Bcl-x [55]. The synergistic effect of STI571 and vincristine may be attributable to their effects on Bcl-x. These findings may provide clues as to new treatment combinations for STI571 with chemotherapy for SCLC. By potentiating the apoptotic effect of the antimicrotubule agents (taxanes and vinca alkaloids), STI571 could represent an important addition to SCLC treatment regimens. In vitro testing is ongoing for cytotoxicity of STI571 combined with different chemotherapeutic agents on SCLC and NSCLC cell lines.

Other potential applications for TK inhibitors might be in the adjuvant setting, or for chemoprevention. About 50% of patients with stage I NSCLC, despite complete surgical resection, die from recurrent disease within 5 years [56]. Seventy percent of recurrences occur outside the chest, indicating that submicroscopic dissemination of cancer cells occurs early in the course of NSCLC [57]. Recent evidence suggests that chemotherapy administered after surgery results in significantly better overall survival and disease-free survival rates [58, 59]. These recent results with cisplatin and uracil and tegafur (UFT) chemotherapy contradict prior data that showed no survival benefit with adjuvant chemotherapy [58–60]. It has been proposed that TK inhibitors may improve adjuvant treatment for stage I NSCLC and lead to improved overall survival. Additionally, a phase IIB/III clinical trial is investigating the effect of the EGFR-TK inhibitor gefitinib on molecular changes in premalignant bronchial lesions in former smokers [61]. The presence of aberrant EGFR-TK activity in all disease stages, combined with the low toxicity and oral administration of EGFR-TK inhibitors, raises the possibility that EGFR-TK inhibitors may have utility for chronic or long-term treatment settings, such as high-risk situations or maintenance after chemotherapy [4, 17].

	FUTURE DIRECTIONS

Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 
As TK inhibitors become available for use in clinical practice, it will be important to identify which patients will respond to these therapies. In the case of Bcr-Abl TK inhibition, the presence of Ph⁺ cells is a good indication of potential responders, although native or acquired resistance can be confounding. The identification of potential responders to EGFR-TK inhibition is not as straightforward, as demonstrated by results of preclinical data with small molecule inhibitors, the complex nature of EGFR-TK activation, and the lack of a standardized assay for measuring EGFR-TK levels or activity in tumors. In the OSI-774 trial, overexpression of the EGFR was required for enrollment, whereas patients in the gefitinib IDEAL trials were enrolled regardless of EGFR expression levels in their tumors. This strategy was based on the high frequency of EGFR expression observed in NSCLC specimens (up to 80%) [7]. Continued investigation is needed to identify useful clinical or diagnostic predictors of responsiveness to EGFR-TK inhibitors, since EGFR expression may not be solely predictive of tumor response. Several ongoing studies with EGFR-TK inhibitors are measuring expression and activation of EGFR and other downstream signaling molecules such as PI3K, Akt, and MAPK in tumor tissue using immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH). The objective of those studies is to establish a profile of potential responders. To date, most studies have shown no correlation between EGFR expression and tumor responses to EGFR-TK inhibitors [62–64]. While EGFR levels may not correlate with response, studies are ongoing to compare the levels of phosphorylated, activated EGFR with tumor responses. In addition, downstream signaling molecules may play an important role in tumor growth and response to targeted agents. Techniques such as IHC and FISH that are able to assess genetic mutations, expression levels, and phosphorylation/activation of various signaling molecules will be valuable in defining subsets of patients who may potentially respond to targeted therapy. Nevertheless, the manageable side-effect profiles of EGFR-TK inhibitors like gefitinib make it possible to try this new approach in patients who have a chance of responding. Continued clinical studies with TK inhibitors are needed to define those patients who are most likely to respond and to provide insight into how TK inhibition can be integrated into current treatment strategies for lung cancer and other common solid tumors.

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Top Learning Objectives Abstract Introduction TKs as Targets for... EGFR-TK in Cancer Bcr-Abl TK: Role in... Potential for TK-Targeted... Future Directions References

 

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