Ack1 Tyrosine Kinase Activation Correlates With Pancreatic Cancer Progression - Download Free Apps2/26/2018 TNK2 gene encodes a non-receptor tyrosine kinase, ACK1. The activation of ACK1 has been observed in. Pancreatic, lung and ovarian cancer cells. Activation of Tyrosine Kinases in Cancer. Of targeted tyrosine kinase (TK) inhibitors for cancer treatment. Drives cancer progression. Kiran Mahajan, PhD Academic. LIneberger Comprehensive Cancer Center. Ack1 tyrosine kinase activation correlates with pancreatic cancer progression. ![]() ![]() TNK2 Available structures Ortholog search: List of PDB id codes,,,,,,,,, Identifiers, ACK, ACK-1, ACK1, p21cdc42Hs, tyrosine kinase non receptor 2 External IDs Targeted by Drug Molecular function • • • • • • • • • • • • • • • Cellular component • • • • • • • • • • • • • Biological process • • • • • • • • • • • • • • Sources: / pattern Orthologs Species Human Mouse RefSeq (mRNA) RefSeq (protein) Location (UCSC) search Activated CDC42 kinase 1, also known as ACK1, is an that in humans is encoded by the TNK2. TNK2 gene encodes a non-receptor tyrosine kinase, ACK1, that binds to multiple receptor tyrosine kinases e.g. EGFR, MERTK, AXL, HER2 and insulin receptor (IR). ACK1 also interacts with Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined. Interactions ACK1 or TNK2 has been shown to with, Androgen receptor or, a tumor suppressor, and. ACK1 interaction with its substrates resulted in their phosphorylation at specific tyrosine residues. ACK1 has been shown to directly phosphorylate AKT at tyrosine 176, AR at Tyrosine 267 and 363, and WWOX at tyrosine 287 residues, respectively. ACK1-AR signaling has also been reported to regulate levels, Clinical relevance ACK1 is a survival kinase and shown to be associated with tumor cell survival, proliferation, hormone-resistance and radiation resistance. The activation of ACK1 has been observed in prostate, breast, pancreatic, lung and ovarian cancer cells. ACK1 transgenic mice, expressing activated ACK1 specifically in prostate gland has been reported; these mice develop prostatic intraepithelial neoplasia (PINs). ACK1 inhibitors Ack1 has emerged as a new cancer target and multiple small molecule inhibitors have been reported. All of these inhibitors are currently in the pre-clinical stage. • Maruyama K, Sugano S (1994). 'Oligo-capping: a simple method to replace the cap structure of eukaryotic mRNAs with oligoribonucleotides'. 138 (1–2): 171–4... • Satoh T, Kato J, Nishida K, Kaziro Y (1996). 'Tyrosine phosphorylation of ACK in response to temperature shift-down, hyperosmotic shock, and epidermal growth factor stimulation'. 386 (2–3): 230–4... • Suzuki Y, Yoshitomo-Nakagawa K, Maruyama K, et al. 'Construction and characterization of a full length-enriched and a 5'-end-enriched cDNA library'. 200 (1–2): 149–56... • Mott HR, Owen D, Nietlispach D, et al. 'Structure of the small G protein Cdc42 bound to the GTPase-binding domain of ACK'. 399 (6734): 384–8... • Eisenmann KM, McCarthy JB, Simpson MA, et al. 'Melanoma chondroitin sulphate proteoglycan regulates cell spreading through Cdc42, Ack-1 and p130cas'. 1 (8): 507–13... • Kato J, Kaziro Y, Satoh T (2000). 'Activation of the guanine nucleotide exchange factor Dbl following ACK1-dependent tyrosine phosphorylation'. 268 (1): 141–7... • Owen D, Mott HR, Laue ED, Lowe PN (2000). 'Residues in Cdc42 that specify binding to individual CRIB effector proteins'. 39 (6): 1243–50... • Kiyono M, Kato J, Kataoka T, et al. 'Stimulation of Ras guanine nucleotide exchange activity of Ras-GRF1/CDC25(Mm) upon tyrosine phosphorylation by the Cdc42-regulated kinase ACK1'. 275 (38): 29788–93... • Linseman DA, Heidenreich KA, Fisher SK (2001). 'Stimulation of M3 muscarinic receptors induces phosphorylation of the Cdc42 effector activated Cdc42Hs-associated kinase-1 via a Fyn tyrosine kinase signaling pathway'. 276 (8): 5622–8... • Teo M, Tan L, Lim L, Manser E (2001). 'The tyrosine kinase ACK1 associates with clathrin-coated vesicles through a binding motif shared by arrestin and other adaptors'. 276 (21): 18392–8... • Kato-Stankiewicz J, Ueda S, Kataoka T, et al. 'Epidermal growth factor stimulation of the ACK1/Dbl pathway in a Cdc42 and Grb2-dependent manner'. 284 (2): 470–7... • Oda T, Muramatsu MA, Isogai T, et al. 'HSH2: a novel SH2 domain-containing adapter protein involved in tyrosine kinase signaling in hematopoietic cells'. 288 (5): 1078–86... • Strausberg RL, Feingold EA, Grouse LH, et al. 99 (26): 16899–903.... • Salomon AR, Ficarro SB, Brill LM, et al. 100 (2): 443–8.... • Ahmed I, Calle Y, Sayed MA, et al. 'Cdc42-dependent nuclear translocation of non-receptor tyrosine kinase, ACK'. 314 (2): 571–9... • Gu Y, Lin Q, Childress C, Yang W (2004). 'Identification of the region in Cdc42 that confers the binding specificity to activated Cdc42-associated kinase'. 279 (29): 30507–13... • Brandenberger R, Wei H, Zhang S, et al. 'Transcriptome characterization elucidates signaling networks that control human ES cell growth and differentiation'. 22 (6): 707–16... • Lougheed JC, Chen RH, Mak P, Stout TJ (2004). 'Crystal structures of the phosphorylated and unphosphorylated kinase domains of the Cdc42-associated tyrosine kinase ACK1'. 279 (42): 44039–45... External links • human gene location in the. • human gene details in the. Abstract 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. I ntroduction 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 ™; Novartis Pharmaceuticals Corporation; East Hanover, NJ), gefitinib (Iressa ®; AstraZeneca Pharmaceuticals LP; Wilmington, DE), and OSI-774 (erlotinib, Tarceva ™; 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. TK s as T argets for A ntitumor T herapy TKs are enzymes that transfer γ-phosphate groups from ATP to the hydroxyl group of tyrosine residues on signal transduction molecules []. 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 []. 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 []. 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 [, ]. 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 []. 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 []. Many of both types of TKs are regularly found to be mutated or expressed at high levels in human malignancies [, ]. 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 [, ]. 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 C ancer 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) [, ]. From precancerous lesions to malignant tumors, elevated EGFR-TK activity has been detected at all stages of tumor progression [, ]. 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 [,, ]. 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 [, ]. 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 []. 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. EGFR-TK activity plays a key role in numerous processes that affect tumor growth and progression, including proliferation, dedifferentiation, inhibition of apoptosis, metastasis (through effects on cell migration, invasiveness, and lack of adhesion dependence), and angiogenesis [,, ]. Signaling through EGFR-TK is pleiotropic both in terms of the multiple signaling pathways that are activated and in terms of the biologic downstream effects, as shown in Figure 1 [,,, ]. Phosphorylated tyrosine residues in the EGFR serve as binding sites for the Grb2/Sos complex, thus activating the Ras/Raf/mitogen-activated protein kinase (MAPK) signaling cascade, which, in turn, influences cell proliferation, migration, and differentiation [,, ]. Recruitment of a second signaling pathway, the phosphatidylinositol 3-kinase pathway (PI3K), results in inhibition of apoptosis mechanisms in tumor cells []. Other key downstream signaling molecules that are influenced by EGFR-TK activity include phospholipase C, Ca 2+/calmodulin-dependent kinases, and the Janus kinase/signal transducer and activator of transcription pathway []. Activity of EGFR-TK also influences tumor angiogenesis by upregulating expression of VEGF and interleukin-8 []. Furthermore, crosstalk with other signaling molecules, such as G-protein-coupled receptors and integrins, increases the range of impact of EGFR-TK []. Activity of EGFR-TK is, therefore, an attractive drug target for inhibiting cancer because of its central role in multiple, fundamental tumor biology processes. Other kinases may be less promising drug targets due to redundancy or compensatory mechanisms in the cell. For example, the activity of only one of the nine known Src family kinases (at least three of which are expressed in most cell types) is needed for intracellular signaling and expression of its function []. Thus, agents that block only one of these Src kinases would not be expected to inhibit Src-mediated cell functions. Inhibitors of EGFR-TK Activity There are several small-molecule EGFR-TK inhibitors approved or in clinical development (Table 2). Some are selective for the EGFR, others inhibit several members of the ErbB family. All act by competing for occupation of the ATP-binding site on the TK domain of the receptor. Two EGFR-TK inhibitors, OSI-774 and gefitinib, have been investigated in phase I, II, and III clinical trials; several other EGFR-TK inhibitors, such as CI-1033 (Pfizer Inc.; New York, NY) and GW572016 (GlaxoSmithKline; Research Triangle Park, NC) are undergoing phase I and II testing []. OSI-774 is a quinazoline EGFR-TK inhibitor in clinical development. In phase I trials, the maximum-tolerated dose of OSI-774 was established at 150 mg/day []. In a randomized phase II trial of 57 patients with stage IIIB or IV NSCLC, OSI-774 was investigated as monotherapy at 150 mg/day []. Patients were required to have tumors in which more than 10% of cells were EGFR positive by immunohistochemistry. In that study population, the majority of patients (42%) had received two prior chemotherapies including a platinum agent. The tumor response rate was 12%, and 34% of treated patients experienced stable disease. The most common adverse events were grade 1 or 2 rash and diarrhea. Further studies of OSI-774 as monotherapy or as combination therapy for advanced NSCLC are ongoing []. Gefitinib was recently approved for use in the U.S., Australia, and Japan for the treatment of advanced NSCLC after prior chemotherapy and has undergone the most extensive clinical investigation of all the EGFR-TK inhibitors. Phase I trials established the maximum-tolerated dose for gefitinib as 700–800 mg/day, with diarrhea as the dose-limiting toxicity [, ]. Tumor responses in a variety of common human solid tumors, including NSCLC and prostate, head and neck, colorectal, and ovarian cancers, were also observed in these heavily pretreated patients [–]. The phase II trials, Iressa Dose Evaluation in Advanced Lung Cancer (IDEAL)-1 and IDEAL-2, compared gefitinib as monotherapy at 250 mg/day with a 500-mg/day dose for previously treated patients with advanced NSCLC. IDEAL-1 ( n = 210) required that patients had received one or two prior chemotherapies including a platinum agent. IDEAL-2 ( n = 216) required that patients had received two or more prior chemotherapies including a platinum agent and docetaxel. Testing for EGFR expression in tumors was not required for entry in these trials [–]. Objective response rates in the IDEAL-1 trial were 18% and 19%, at 250 mg/day and 500 mg/day, respectively, and were 12% and 9%, respectively, in the IDEAL-2 trial. One-quarter to one-third of patients achieved stable disease, and many patients in these monotherapy trials experienced relief of lung-cancer-related symptoms such as breathlessness, coughing, and chest pain. The most frequent drug-related adverse events were grade 1 or 2 skin rash and diarrhea. In the adult, EGFR-TK activity plays a restricted role in skin and gastrointestinal tract cancers, suggesting an EGFR inhibition mechanism for such effects [–]. These adverse effects may be common to the EGFR-TK inhibitor class of agents []. 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 []. 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. B cr-A bl TK: R ole in C ancer and E ffects of TK I nhibition 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) []. 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 [, ]. 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. Drug-related adverse effects include nausea, vomiting, myalgias, edema, diarrhea, and, less commonly, anemia, thrombocytopenia, neutropenia, and myelosuppression [, ]. In at least the initial stages of treatment, STI571 has been very effective in inhibiting progression of CML and Ph + adult ALL [, ]. 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 []. 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 [, ]. 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 []. By contrast, patients treated in the earlier, chronic phase of the disease developed drug resistance only rarely and often demonstrated prolonged remissions []. 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. STI571 is not specific for the Bcr-Abl TK, and its action extends to the c-kit and PDGFR TKs []. The c-kit TK is important in a number of cell types, including hematopoietic stem cells, mast cells, intraepithelial lymphocytes, melanocytes, and gametocytes []. Mutations leading to ligand-independent, constitutive activation of c-kit are associated with some rare human cancers, including gastrointestinal stromal tumors (GISTs) and mast cell/myeloid leukemia []. An autocrine growth loop involving c-kit and its ligand, stem cell factor, also appears to characterize approximately 70% of SCLCs []. STI571 was recently approved for the treatment of c-kit-positive advanced and/or surgically unresectable GISTs and is undergoing trials for the treatment of SCLC. Autocrine PDGFR stimulation is found in several human tumor types, including dermatofibrosarcoma protuberans, giant cell fibroblastoma, and glioblastoma, each of which responds to STI571 with growth inhibition or apoptosis in vitro and in xenograft models [, ]. Chronic myelomonocytic leukemia is characterized by a translocation that yields a Tel-PDGFR fusion protein with constitutive TK activity. These tumor cells are also growth inhibited in vitro by STI571 []. In addition, approximately 50%–60% of resected NSCLC specimens express PDGFR [, ]. Signaling through PDGFR was shown to increase interstitial fluid pressure that subsequently leads to interstitial hypertension and a poor uptake of anticancer drugs. It has been shown that inhibition of PDGFR with STI571 decreased the interstitial hypertension and increased capillary to interstitium transport of 51Cr-EDTA []. These data suggest that STI571 may be applicable as a lung cancer treatment, as a novel strategy to increase the uptake of chemotherapeutic agents. P otential for TK-T argeted T herapies A cross T umor T ypes and S tages 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 []. 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 []. Most cases of NSCLC are locally advanced or metastatic at initial presentation []. 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 []. 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 []. 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 []. 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 []. Seventy percent of recurrences occur outside the chest, indicating that submicroscopic dissemination of cancer cells occurs early in the course of NSCLC []. Recent evidence suggests that chemotherapy administered after surgery results in significantly better overall survival and disease-free survival rates [, ]. These recent results with cisplatin and uracil and tegafur (UFT) chemotherapy contradict prior data that showed no survival benefit with adjuvant chemotherapy [–]. 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 []. 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 [, ]. F uture D irections 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%) []. 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 [–]. 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. • © AlphaMed Press.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. Archives
March 2018
Categories |