Annals of Oncology Advance Access originally published online on April 3, 2008
Annals of Oncology 2008 19(7):1219-1223; doi:10.1093/annonc/mdn048
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
reviews |
Src as a potential therapeutic target in non-small-cell lung cancer
1 Center for Cancer Research, National Cancer Institute, Bethesda, USA
2 Dipartimento di Oncologia ed Ematologia, Istituto Clinico Humanitas, Rozzano, Italy
* Correspondence to: Dr G. Giaccone, Center for Cancer Research, National Cancer Institute, 10 Center Drive, Building 10, Room 12N226, Bethesda MD 20892-1906, USA. Tel: +1 301 4023415; Fax: +1 301 4020172; E-mail: giacconeg{at}mail.nih.gov
 |
Abstract |
|---|
 Top Abstract introductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Lung cancer is the most common cause of cancer-related death, with non-small-cell lung cancer (NSCLC) accounting for 80%–85% of all cases. Although survival rates are reasonably good for patients diagnosed with very early disease, the majority of patients present with advanced disease. For these patients, palliation and improvements in quality of life are the primary goals of therapy. Although chemotherapeutic agents remain the cornerstone of first-line therapy, these agents have limited use in patients who have relapsed and have metastatic disease. Therefore, new strategies are required to improve survival and quality of life in this setting. With the substantial advances in our understanding of tumour biology, it has been possible to identify signalling pathways involved in mediating tumour growth and progression. These pathways offer targets for new biological agents such as small molecule inhibitors and monoclonal antibodies. One such target is Src, a tyrosine kinase that is involved in multiple aspects of tumorigenesis including proliferation, migration and angiogenesis. Increased levels of Src expression have been found in a range of cancers, especially breast, colorectal, prostate and lung. Preliminary preclinical data and pharmacodynamic data suggest that Src inhibition is a viable therapeutic option in the treatment of advanced NSCLC.
Key words: non-small cell lung cancer, Src, targeted therapy, tyrosine kinase
|
introduction |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Lung cancer will cause an estimated 31% of cancer deaths in men and 26% of cancer deaths in women in the United States in 2007 [1]. Although lung cancer mortality rates have been falling for men since the 1990s, rates in women are continuing to rise. In recent years, more women have died of lung cancer than breast and colorectal cancer combined [1]. The situation in Europe is similar, with lung cancer being the most common cause of death from cancer in men, although breast cancer is responsible for more deaths in women [2]. Non-small-cell lung cancer (NSCLC) accounts for
80%–85% of cases, with the remaining 15%–20% of patients presenting with small-cell lung cancer. Current first-line treatments for patients with NSCLC include chemotherapy with a platinum agent in combination with a taxane or other cytotoxic agent such as gemcitabine or vinorelbine. Many patients with advanced NSCLC, however, have only a partial response to initial chemotherapy, and even those who do respond will subsequently progress. Weekly docetaxel is one of the three standard second-line therapies for patients who fail to respond to, or who are unable to tolerate, platinum-based regimens. Pemetrexed has recently demonstrated clinically equivalent efficacy to docetaxel, but with significantly fewer side effects. In addition, the epithelial growth factor receptor (EGFR) inhibitor erlotinib has also been approved for the treatment of locally advanced or metastatic NSCLC, after failure of one or two chemotherapy regimens. Nonetheless, the prognosis for patients with locally advanced or metastatic NSCLC remains poor. Indeed, the 5-year survival rate for all stages of lung cancer combined is 15% [3] with recent survival gains with chemotherapy and radiotherapy measured in terms of months. Therefore, as with other cancers, specific targeting of aberrant signalling or metabolic processes involved in tumorigenesis has become a new focus of NSCLC therapy. The cellular tyrosine kinase, Src, offers a particularly promising molecular target for anticancer therapy, as inhibition of Src leads to inhibition of multiple signalling pathways. Src tyrosine family kinases are key regulators of cellular proliferation, survival, motility and invasiveness [4]. This review will discuss the role of Src in the development and maintenance of NSCLC and its potential role in targeted therapy for this disease.
|
the role of Src in tumorigenic and metastatic processes |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Aberrant Src activation has been implicated in the development of numerous human cancers, including cancer of the lung, prostate, pancreas, breast and colon [5]. Src is a member of the Src family of tyrosine kinases, which consists of nine known members: Src, Yes, Fgr, Yrk, Fyn, Lyn, Hck, Lck and Blk. These proteins are nonreceptor tyrosine kinases that are localised within the cytosol and transduce signals between cell surface proteins, other intracellular proteins and transcription factors [6]. Under physiologic conditions, Src is normally maintained in an inactive state—via phosphorylation of an amino acid near the C-terminus of the protein [7]. Dephosphorylation of this amino acid changes the conformation of Src and results in the autophosphorylation of another tyrosine residue within the activation loop of the protein. The protein is then fully active and able to interact with other proteins.
Increased Src activity up-regulates a number of signalling cascades associated with tumour development and progression leading to increased cell growth, migration and invasion (Figure 1). In epithelial tumours, the levels of expression or activation generally correlate with disease progression [8]. In addition, Src activity is higher in metastatic tissue compared with primary tumours and cells with limited metastatic potential [9]. Src mediates epithelial-mesenchymal transition (EMT), which changes the tumour tissue architecture and enables metastatic progression [10]. C-Met-mediated activation of Src causes down-regulation of E-cadherin, an event that is critical for EMT and tumour invasion [10].
|
|
Src signalling in NSCLC |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Increased expression of Src has been reported in 60%–80% of adenocarcinomas and bronchioloalveolar cancers and in 50% of squamous cell carcinomas isolated from patients with NSCLC [11]. In addition, high levels of Src kinase activity have been reported in NSCLC, particularly adenocarcinomas, with the degree of kinase activity correlating with tumour size [12]. In a study of 60 cancer cell lines, the NSCLC lines had the highest median Src activity [13]. Furthermore, the mitogenic effects of both nicotine [14] and asbestos [15] in NSCLC cells are likely to involve the activation of Src.
Src may stimulate tumorigenesis in NSCLC in a variety of ways. Schematic Src-signalling pathways are shown in Figure 2. One of the most well-described Src-mediated pathways involves signal transducer and activator of transcription (STAT)-3 and focal adhesion kinase (FAK), both of which are involved in tumour survival [16, 17]. STATs are transcription factors that mediate expression of genes involved in cell cycle progression and apoptosis. FAK is a tyrosine kinase involved in integrin signalling, and elevated FAK levels have been associated with increased cell motility, invasion and proliferation in cancer cells [18]. Src-mediated constitutive STAT-3 activity has been found in multiple NSCLC lines [16]. Studies show that activation of STAT-3 and FAK by Src is required for anchorage-dependent and -independent cell growth in a range of human tumours including NSCLC [16, 17]. In addition, in NSCLC, stimulation of STAT-3 by epidermal growth factor (EGF), interleukin 6 and hepatocyte-derived growth factor all require Src activity [16]. Another growth factor involved in Src-STAT-3 signalling is prostaglandin E2, which activates Src, and results in growth of lung cancer cells [19]. Src also activates the VEGF pathway via STAT-3 [20] and in response to hypoxia in human lung adenocarcinoma cells, thus increasing the blood supply to the oxygen-starved tumour [21].
|
In human lung tumour cells, Src activity is also associated with inhibition of anoikis—a form of cell death induced by the detachment of adherent cells from their substratum [22]. Following detachment from the primary tumour, Src activity is increased in adenocarcinoma cells. It is thought that up-regulation of Src is able to compensate for the loss of survival signals from the cell matrix. When Src is inhibited, the detached cells undergo anoikis.
|
Src interaction with EGFR |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Src offers a particularly promising molecular target for anticancer therapy, as inhibition of Src leads to inhibition of multiple signalling pathways, including those mediated by members of the EGFR family. The EGFR family, also known as the ErbB family, is a group of receptor tyrosine kinases implicated in the development of cancer, including NSCLC. Src is able to hyperactivate EGFR by phosphorylating multiple sites, including a unique tyrosine residue Y845 to promote oncogenesis via STAT-5b, independent of the ERK2 pathway [23–25]. Inhibition of Src can reverse the transformed phenotype of cells overexpressing EGFR and HER-2, another member of the ErbB family [26].
Constitutive activation of EGFR is found in a subset of NSCLC tumours that are dependent on EGFR for survival, and selective inhibition of EGFR has demonstrated some success in the treatment of NSCLC.
Studies in nude mice show that Src and EGFR work synergistically giving rise to a particularly aggressive phenotype [27]. Tumours in nude mice inoculated with Src/EGFR overexpressing fibroblasts were significantly larger than those inoculated with fibroblasts overexpressing either Src or EGFR alone [27]. Src is also required for both EGF- and LPA-induced mitogenesis via EGFR [23, 24]. Furthermore, Src activation of EGFR results in enhanced cell survival via cytochrome c oxidase subunit II [28]. Studies in breast cancer show that Src is necessary for integrin transactivation of EGFR, and couples EGFR to G protein-coupled receptors [29, 30]. Src may also prevent down-regulation of EGFR in tumour cells [31].
Inhibition of nonreceptor tyrosine kinase Src in EGFR-dependent NSCLC cell lines results in shut down of the EGFR-dependent survival network and induction of apoptosis [32]. The tyrosine kinase inhibitor (TKI) dasatinib, which targets Src family kinases, has minimal effects on apoptosis but arrests growth and prevents tumour invasion in NSCLC cells expressing wild-type or EGFR mutants that are resistant to EGFR inhibition [32, 33]. This is particularly promising as many EGFR-dependent tumours, despite initially good response rates to EGFR inhibitors, ultimately acquire resistance. This may be through additional mutations in EGFR or other mechanisms [34], such as activation of P-AKT and ERK via Src [35]. In these patients, the addition of chemotherapy to EGFR inhibitor regimens has no effect on recurrence [36], and new therapies are required to improve clinical outcomes. Src inhibition may be an appropriate treatment in this setting, and additional in vitro studies of tumour cells with mutations resistant to EGFR inhibition are warranted.
Activation of Src induces the loss of E-cadherin complexes. This loss has been shown to correlate with resistance to EGFR TKIs. In lung cancer cell lines, restoring E-cadherin expression increased sensitivity to EGFR TKIs [37]. Additionally, in an analysis of E-cadherin expression in patients with NSCLC, those with strong E-cadherin staining had a significantly longer time to progression and a trend towards longer survival with erlotinib plus chemotherapy compared with chemotherapy alone [38].
|
targeting multiple signalling pathways in NSCLC: the therapeutic value of Src inhibition |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Response rates in patients treated with selective targeted agents, particularly in unselected patients, tend to be low due to the fact that there is no single common molecular event initiating tumorigenesis. NSCLC, like most cancers, is a heterogeneous disease, with highly complex and often redundant signalling pathways. A specific molecular aberration may only be present in a subset of tumours. Therefore, targeting multiple pathways simultaneously may be a more effective strategy than targeting just a single one. Multiple pathways can be targeted by using a combination of single-targeted agents, such as the anti-VEGF monoclonal antibody bevacizumab and the EGFR TKI erlotinib (currently in phase III trials of patients with advanced NSCLC) or by using a multitargeted agent. As Src overexpression and/or overactivity appears to have a role in tumour development and metastases in NSCLC, and Src mediates multiple oncogenic pathways, compounds that can inhibit Src signalling are of particular clinical interest. A number of Src inhibitors are currently being investigated as potential therapies for NSCLC (Table 1).
|
Dasatinib (SPRYCEL®, Bristol-Myers Squibb; BMS-354825), a potent, multitargeted, oral inhibitor of Src family kinases, Bcr-Abl, Kit, platelet-derived growth factor receptor (PDGFR)β and Eph receptors, has clinical efficacy in patients with Philadelphia chromosome-positive chronic myeloid leukaemia (CML) and acute lymphoblastic leukaemia [39–41]. Dasatinib has also shown effects in solid tumours. In preclinical studies, NSCLC cells treated with dasatinib show decreased cell growth, substrate-dependent changes in cell morphology and changes in downstream signalling leading to a reduced capability for invasion [32, 33] (Figure 3). In EGFR-dependent NSCLC cell lines, treatment with dasatinib results in apoptosis [32]. In the clinical setting, initial pharmacodynamic data have demonstrated that patients with solid tumours exposed to dasatinib show substantially inhibited Src activity [42]. Furthermore, no dose-limiting toxicity was observed in a dose-escalation study in patients with solid tumours [43].
|
AZD0530 is an orally active dual Src/Abl inhibitor that has been shown to be active in preclinical models of CML and solid tumours. In multiple NSCLC lines, AZD0530 blocked cell growth in a time- and dose-dependent manner [44]. AZD0530 also induced apoptosis in 10%–22% of cells at micromolar concentrations. However, in H69 and H526 cells, growth inhibition by AZD0530 was limited (IC50 > 100 µM) [44]. AZD0530 has also been shown to inhibit the invasiveness and motility of tamoxifen-resistant breast cancer cells in vitro [45] and to prevent metastasis in bladder and pancreatic tumour models [46].
SKI-606 (bosutinib) is another orally active dual Src/Abl inhibitor with preclinical activity in CML and solid tumours. In a preclinical study, SKI-606 induced apoptosis in the EGFR-dependent NSCLC cell lines HCC827 and H3255 [47]. Preliminary clinical data from a phase I study in patients with advanced malignant solid tumours, including NSCLC, suggest that SKI-606 may be active in patients with NSCLC [48]. Further investigations are ongoing.
XL999 is a small molecule inhibitor of multiple kinases including Src and receptor tyrosine kinases vascular endothelial growth factor receptor (VEGFR2), PDGFR, Kit and fibroblast growth factor (FGFR1). A phase I trial has shown preliminary evidence of clinical activity in patients with advanced solid malignancies [49]. A phase II trial of XL999 in advanced pretreated NSCLC was initiated in December 2005. This study, however, was suspended in November 2006 because of concerns regarding cardiovascular safety. In all, 16 of 131 patients (12%) experienced serious cardiovascular adverse events.
M475271 is an orally available inhibitor of Src kinase that reduces cellular proliferation and VEGF-mediated neovascularisation in lung adenocarcinoma cell lines [50]. In addition, in M475271-treated natural killer cell-depleted mice, subcutaneous tumours showed retarded growth and lung metastases were inhibited.
The results from these preliminary studies support Src inhibition as a valid strategy for the treatment of solid tumours, and the results of ongoing single agent and combination trials of Src inhibitors in NSCLC are eagerly awaited. Further data from prospective phase III trials will be required to confirm the efficacy of these agents in improving clinical outcomes in patients with NSCLC.
|
conclusions |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Aberrant Src expression and activity occur in many NSCLC tumours, but the clinical significance of this oncogene in the development and proliferation of tumours remains to be quantified. It is clear that the interaction of Src with factors such as FAK and VEGF helps to promote tumour growth and metastasis. In addition, synergy between Src and other tyrosine kinases such as EGFR appears to be an important mechanism for stimulating tumour growth. Preclinical studies suggest that Src inhibition may play a role in treating selected patients with NSCLC. There may also be a role for anti-Src therapy in combination with other targeted treatments. For example, dual attack with Src inhibitors in combination with EGFR inhibitors may prevent the development of EGFR inhibitor-resistant clones. The heterogeneity of NSCLC means that defining predictors of prognosis and selecting appropriate patients for treatment present a clear challenge in this new era of targeted therapy.
|
funding |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Bristol-Myers Squibb.
|
Acknowledgements |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
Writing and editorial support was provided by K. Allen-O'Rourke.
Received for publication October 15, 2007. Revision received January 29, 2008. Accepted for publication February 1, 2008.
|
References |
|---|
|
TopAbstractintroductionthe role of Src...Src signalling in NSCLCSrc interaction with EGFRtargeting multiple signalling...conclusionsfundingAcknowledgementsReferences |
|---|
1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin (2007) 57:43–66.
2. Ferlay J, Autier P, Boniol M, et al. Estimates of the cancer incidence and mortality in Europe in 2006. Ann Oncol (2007) 18:581–592.
3. American Cancer Society. Cancer Facts and Figures 2006 (2006).
4. Zeng L, Si X, Yu WP, et al. PTP alpha regulates integrin-stimulated FAK autophosphorylation and cytoskeletal rearrangement in cell spreading and migration. J Cell Biol (2003) 160:137–146.[CrossRef][Web of Science][Medline]
5. Summy JM, Gallick GE. Src family kinases in tumour progression and metastasis. Cancer Metastasis Rev (2003) 22:337–358.[CrossRef][Web of Science][Medline]
6. Bjorge JD, Jakymiw A, Fujita DJ. Selected glimpses into the activation and function of Src kinase. Oncogene (2000) 19:5620–5635.[CrossRef][Web of Science][Medline]
7. MacAuley A, Cooper JA. Structural differences between repressed and depressed forms of p60c-src. Mol Cell Biol (1989) 9:2648–2656.
8. Irby RB, Yeatman TJ. Role of Src expression and activation in human cancer. Oncogene (2000) 19:5636–5642.[CrossRef][Web of Science][Medline]
9. Mao W, Irby R, Coppola D, et al. Activation of c-Src by receptor tyrosine kinases in human colon cancer cells with high metastatic potential. Oncogene (1997) 15:3083–3090.[CrossRef][Web of Science][Medline]
10. Guarino M, Rubino B, Ballabio G. The role of epithelial-mesenchymal transition in cancer pathology. Pathology (Phila) (2007) 39:305–318.
11. Mazurenko NN, Kogan EA, Zborovskaya IB, et al. Expression of pp60c-src in human small cell and non-small cell lung carcinomas. Eur J Cancer (1992) 28:372–377.[CrossRef][Medline]
12. Masaki T, Igarashi K, Tokuda M, et al. pp60c-src activation in lung adenocarcinoma. Eur J Cancer (2003) 39:1447–1455.[CrossRef][Web of Science][Medline]
13. Budde RJ, Ke S, Levin VA. Activity of pp60c-src in 60 different cell lines derived from human tumours. Cancer Biochem Biophys (1994) 14:171–175.[Web of Science][Medline]
14. Dasgupta P, Rastogi S, Pillai S, et al. Nicotine induces cell proliferation by beta-arrestin-mediated activation of Src and Rb-Raf-1 pathways. J Clin Invest (2006) 116:2208–2217.[CrossRef][Web of Science][Medline]
15. Scapoli L, Ramos-Nino ME, Martinelli M, et al. Src-dependent ERK5 and Src/EGFR-dependent ERK1/2 activation is required for cell proliferation by asbestos. Oncogene (2004) 23:805–813.[CrossRef][Web of Science][Medline]
16. Song L, Turkson J, Karras JG, et al. Activation of Stat3 by receptor tyrosine kinases and cytokines regulates survival in human non-small cell carcinoma cells. Oncogene (2003) 22:4150–4165.[CrossRef][Web of Science][Medline]
17. Laird AD, Li G, Moss KG, et al. Src family kinase activity is required for signal tranducer and activator of transcription 3 and focal adhesion kinase phosphorylation and vascular endothelial growth factor signaling in vivo and for anchorage-dependent and -independent growth of human tumour cells. Mol Cancer Ther (2003) 2:461–469.
18. Owens LV, Xu L, Craven RJ, et al. Overexpression of the focal adhesion kinase (p125FAK) in invasive human tumours. Cancer Res (1995) 55:2752–2755.
19. Yamaki T, Endoh K, Miyahara M, et al. Prostaglandin E2 activates Src signaling in lung adenocarcinoma cell via EP3. Cancer Lett (2004) 214:115–120.[CrossRef][Web of Science][Medline]
20. Eliceiri BP, Paul R, Schwartzberg PL, et al. Selective requirement for Src kinases during VEGF-induced angiogenesis and vascular permeability. Mol Cell (1999) 4:915–924.[CrossRef][Web of Science][Medline]
21. Sato M, Tanaka T, Maeno T, et al. Inducible expression of endothelial PAS domain protein-1 by hypoxia in human lung adenocarcinoma A549 cells. Role of Src family kinases-dependent pathway. Am J Respir Cell Mol Biol (2002) 26:127–134.
22. Wei L, Yang Y, Zhang X, et al. Altered regulation of Src upon cell detachment protects human lung adenocarcinoma cells from anoikis. Oncogene (2004) 23:9052–9061.[CrossRef][Web of Science][Medline]
23. Kloth MT, Laughlin KK, Biscardi JS, et al. STAT5b, a mediator of synergism between c-Src and the epidermal growth factor receptor. J Biol Chem (2003) 278:1671–1679.
24. Tice DA, Biscardi JS, Nickles AL, et al. Mechanism of biological synergy between cellular Src and epidermal growth factor receptor. Proc Natl Acad Sci USA (1999) 96:1415–1420.
25. Stover DR, Becker M, Liebetanz J, et al. Src phosphorylation of the epidermal growth factor receptor at novel sites mediates receptor interaction with Src and P85 alpha. J Biol Chem (1995) 270:15591–15597.
26. Karni R, Jove R, Levitzki A. Inhibition of pp60c-Src reduces Bcl-XL expression and reverses the transformed phenotype of cells overexpressing EGF and HER-2 receptors. Oncogene (1999) 18:4654–4662.[CrossRef][Web of Science][Medline]
27. Maa MC, Leu TH, McCarley DJ, et al. Potentiation of epidermal growth factor receptor-mediated oncogenesis by c-Src: implications for the etiology of multiple human cancers. Proc Natl Acad Sci USA (1995) 92:6981–6985.
28. Boerner JL, Demory ML, Silva C, et al. Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome c oxidase subunit II. Mol Cell Biol (2004) 24:7059–7071.
29. Biscardi JS, Ishizawar RC, Silva CM, et al. Tyrosine kinase signalling in breast cancer: epidermal growth factor receptor and c-Src interactions in breast cancer. Breast Cancer Res (2000) 2:203–210.[CrossRef][Web of Science][Medline]
30. Prenzel N, Zwick E, Daub H, et al. EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature (1999) 402:884–888.[Medline]
31. Bao J, Gur G, Yarden Y. Src promotes destruction of c-Cbl: implications for oncogenic synergy between Src and growth factor receptors. Proc Natl Acad Sci USA (2003) 100:2438–2443.
32. Song L, Morris M, Bagui T, et al. Dasatinib (BMS-354825) selectively induces apoptosis in lung cancer cells dependent on epidermal growth factor receptor signaling for survival. Cancer Res (2006) 66:5542–5548.
33. Johnson FM, Saigal B, Talpaz M, et al. Dasatinib (BMS-3548285) tyrosine kinase inhibitor suppresses invasion and induces cell cycle arrest and apoptosis of head and neck squamous cell carcinoma and non-small cell lung cancer cell. Clin Cancer Res (2005) 11:6924–6932.
34. Haber DA, Bell DW, Sordella R, et al. Molecular targeted therapy of lung cancer: EGFR mutations and response to EGFR inhibitors. Cold Spring Harb Symp Quant Biol (2005) 70:419–426.[CrossRef][Medline]
35. Qin B, Ariyama H, Baba E, et al. Activated Src and Ras induce gefitinib resistance by activation of signaling pathways downstream of epidermal growth factor receptor in human gallbladder adenocarcinoma cells. Cancer Chemother Pharmacol (2006) 58:577–584.[CrossRef][Web of Science][Medline]
36. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol (2005) 23:5892–5899.
37. Witta SE, Gemmill RM, Hirsch FR, et al. Restoring E-cadherin expression increases sensitivity to epidermal growth factor receptor inhibitors in lung cancer cell lines. Cancer Res (2006) 66:944–950.
38. Yauch RL, Januario T, Eberhard DA, et al. Epithelial versus mesenchymal phenotype determines in vitro sensitivity and predicts clinical activity of erlotinib in lung cancer patients. Clin Cancer Res (2005) 11:8686–8698.
39. Cortes J, Rousselot P, Kim DW, et al. Dasatinib induces complete hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukaemia in blast crisis. Blood (2007) 109:3207–3213.
40. Hochhaus A, Kantarjian HM, Baccarani M, et al. Dasatinib induces notable hematologic and cytogenetic responses in chronic-phase chronic myeloid leukaemia after failure of imatinib therapy. Blood (2007) 109:2303–2309.
41. Guilhot F, Apperley J, Kim DW, et al. Dasatinib induces significant hematologic and cytogenetic responses in patients with imatinib-resistant or -intolerant chronic myeloid leukaemia in accelerated phase. Blood (2007) 109:4143–4150.
42. Luo FR, Barrett Y, Ji P, et al. Dasatinib (BMS-354825) pharmacokinetics correlate with pSRC pharmacodynamics in phase I studies of patients with cancer (CA180002, CA180003). J Clin Oncol (2006) 24:18s. (Abstr 3046).[CrossRef]
43. Evans TR, Morgan JA, van den Abbeele AD, et al. Phase I dose-escalation study of the SRC and multi-kinase inhibitor BMS-354825 in patients (pts) with GIST and other solid tumours. J Clin Oncol (2005) 23:16s. (Abstr 3034).
44. Gautschi O, Purnell P, Evans J, et al. Preclinical evaluation of the dual specific Src/Abl kinase inhibitor AZD0530 in lung cancer. J Clin Oncol (2006) 24:18s. (Abstr 13108).[CrossRef]
45. Hiscox S, Morgan L, Green TP, et al. Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res Treat (2006) 97:263–274.[CrossRef][Web of Science][Medline]
46. Hennequin LF, Allen J, Breed J, et al. N-(5-chloro-1,3-benzodioxol-4-yl)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5- (tetrahydro-2H-pyran-4-yloxy)quinazolin-4-amine, a novel, highly selective, orally available, dual-specific c-Src/Abl kinase inhibitor. J Med Chem (2006) 49:6465–6488.[CrossRef][Web of Science][Medline]
47. Zhang J, Kalyankrishna S, Wislez M, et al. SRC-family kinases are activated in non-small cell lung cancer and promote the survival of epidermal growth factor receptor-dependent cell lines. Am J Pathol (2007) 170:366–376.
48. Messersmith WA, Krishnamurthi S, Hewes BA, et al. Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor: preliminary results from a phase 1 study in patients with advanced malignant solid tumours. J Clin Oncol (2007) 25:18S. (Abstr 3552).
49. Cooper J, Mita MM, Curtright J, et al. A phase I study examining weekly dosing and pharmacokinetics (PK) of a novel spectrum selective kinase inhibitor, XL999, in patients (pts) with advanced solid malignancies (ASM). J Clin Oncol (2006) 24:18s. (Abstr 13024).[CrossRef]
50. Zheng R, Yano S, Matsumori Y, et al. SRC tyrosine kinase inhibitor, m475271, suppresses subcutaneous growth and production of lung metastasis via inhibition of proliferation, invasion, and vascularization of human lung adenocarcinoma cells. Clin Exp Metastasis (2005) 22:195–204.[CrossRef][Web of Science][Medline]
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Tyryshkin, F. M. Gorgun, E. A. Fattah, T. Mazumdar, L. Pandit, S. Zeng, and N. T. Eissa Src Kinase-mediated Phosphorylation Stabilizes Inducible Nitric-oxide Synthase in Normal Cells and Cancer Cells J. Biol. Chem., January 1, 2010; 285(1): 784 - 792. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Ceppi, M. Papotti, V. Monica, M. L. Iacono, S. Saviozzi, M. Pautasso, S. Novello, S. Mussino, E. Bracco, M. Volante, et al. Effects of Src kinase inhibition induced by dasatinib in non-small cell lung cancer cell lines treated with cisplatin Mol. Cancer Ther., November 1, 2009; 8(11): 3066 - 3074. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||