Small cell lung cancer (SCLC) is an aggressive cancer characterized by several autocrine growth mechanisms including stem cell factor and its receptor c-Kit. In order to arrive at potentially new and novel therapy for SCLC, we have investigated the effects of the tyrosine kinase inhibitor, STI 571, on SCLC cell lines. It has been previously reported that STI 571 does not only inhibit cellular Abl tyrosine kinase activity but also the PDGF receptor and c-Kit tyrosine kinases at similar concentrations (approximately 0.1 μM). There is no expression of the PDGF-receptor, and the Abl kinase is not activated by SCLC, but over 70% of SCLC contain the c-Kit receptor. Utilizing this preliminary data, we have determined that three (NCI-H69, NCI-H146 and NCI-H209) of five (including NCI-H82 and NCI-H249) SCLC cell lines had detectable c-Kit receptors and were inhibited in growth and viability at concentrations 1–5 μM of STI 571 after 48 h of treatment. The SCLC cell lines, NCI-H69, NCI-H146 and NCI-H209, showed a dose-response (tested between 0.1–10 μM) inhibition of tyrosine phosphorylation of c-Kit as well as in vitro kinase activity (at 5 μM) of c-Kit in response to STI 571. STI 571 inhibited cell motility, as assessed by time-lapsed video microscopy, within 6 h of STI 571 treatment (5 μM). STI 571 also decreased intracellular levels of reactive oxygen species (ROS) by at least 60%, at a concentration (5 μM) that also inhibited cell growth. Cell cycle analysis of STI 571 responsive cells showed that cells were generally slowed in G2/M phase, but there was no arrest at G1/S. A downstream phosphorylation target of c-Kit, Akt, was not phosphorylated in response to stem cell factor in the presence of STI 571. These data imply that STI 571 inhibits growth of SCLC cells through a mechanism that involves inactivation of the tyrosine kinase c-Kit. The effectiveness of STI 571 in this study suggests this drug may be useful in a clinical trial, for patients with SCLC.
Small cell lung cancer (SCLC) composes 16% of all lung cancers in the US and causes significant morbidity and mortality in both the US, as well as in the world (Chute et al., 1999). SCLC metastasizes outside the chest two-thirds of the time at clinical presentation, and only 7% of these patients are alive at 5 years from the start of treatment (Chute et al., 1999).
Autocrine growth loops with growth factors and their receptors have been identified in small cell lung cancer cells (Johnson and Kelley, 1995). The most extensively studied growth loop has been bombesin-like peptides, gastrin releasing peptide and neuromedin B and their three receptors. A monoclonal antibody (2A11) directed against the bombesin-like peptides, gastrin releasing peptide and neuromedin B, has both in vitro and in vivo antitumor activity SCLC (Chaudhry et al., 1999). The administration of 2A11 has caused a complete remission in a patient with relapsed small cell lung cancer supporting the development of agents which inhibit autocrine growth loops as therapeutic agents (Chaudhry et al., 1999).
More recently, it has been identified that SCLC also contains receptor tyrosine kinases that may be important targets for therapies (Johnson and Kelley, 1995). Over 70% of SCLC cell lines and tumors coexpress the c-Kit receptor and its ligand stem cell factor (Hibi et al., 1991). The development of small molecules, which inhibit the specific tyrosine kinase receptor c-Kit, offers another way of potentially inhibiting autocrine growth loops in small cell lung cancer.
Receptor tyrosine kinase inhibition may be opportune targets for preventing progression of SCLC. A tyrosine kinase inhibitor, STI 571, was developed as an ATP competitive inhibitor of the Abl protein kinase (Druker et al., 1996). This tyrosine kinase inhibitor STI 571 (formerly known as CGP57148B, Novartis Pharmaceuticals) was initially shown to inhibit BCR/ABL kinase activity and chronic myelogenous leukemia cells growth, and viability of cells transformed by Abl oncogenes (Sawyers and Druker, 1999). This drug has most recently been shown to be effective in a phase I trial for patients with relapsed CML, with 23 of 24 patients attaining complete hematologic responses for at least 4 weeks at doses of 300 mg or greater (Druker et al., 1999). The clinical efficacy of blocking the BCR/ABL TK with STI 571 has led us to study STI 571 in SCLC. STI 571 inhibits not only the kinase activity of Abl, but also the kinase activity of PDGFR and c-Kit (Carroll et al., 1997). SCLC cells have been shown to have activated kinases including a target of STI 571, c-Kit (Krystal et al., 1996). This information led us to study the novel compound STI 571 to determine its effect on SCLC cell line growth and viability. We have determined the viability of several SCLC cell lines in response to STI 571; as well determine the biological consequences of treatment of these cell lines with the novel tyrosine kinase inhibitor.
STI 571 decreases viability for some SCLC cell lines
The novel tyrosine kinase inhibitor, STI 571, was used to determine its effects on viability of SCLC cell lines. Viability was assessed by trypan blue exclusion. In preliminary studies, we had determined that effective growth inhibition effects by STI 571 occurred within 48 h, and thus viability of the various cell lines was determined at the various concentrations of STI 571 at 48 h. The SCLC cell lines NCI-H69 and NCI-H146 had a dose response to STI 571 at 48 h (Figure 1). In contrast, the viability of NCI-H82 and NCI-H249 was not inhibited by concentrations of up to 10 μM of STI 571. Concentration at 20 μM or above appeared to have non-specific effects on viability. K562 cell lines contain an activated Abl tyrosine kinase secondary to the 9 : 22 translocation (Philadelphia chromosome) with the characteristic BCR/ABL fusion protein. The cell line, BLIN-1, does not contain a BCR/ABL translocation. STI 571 inhibited the growth of K562 with the activated ABL tyrosine kinase (used as a positive control), and it had no effect on the growth of BLIN-1 (used as a negative control). Due to difficulty in counting the H209 cells, these cells also had an IC50 of approximately 1 μM concentration of STI 571 (as visually determined by trypan blue exclusion and by MTT assay), same as NCI-H69 and NCI-H146 cell lines.
Biological effects of STI 571 on responsive SCLC cell lines
STI 571 inhibited the growth of some SCLC cell lines, and we have further determined the effects on other biological functions, such as cell motility, cell cycle, and formation of reactive oxygen species. We have specifically focused on NCI-H69 as being responsive and NCI-H249 as not responsive to STI 571 in these experiments.
As we have shown previously, the introduction of the potent tyrosine kinase BCR/ABL into hematopoietic cells such as Ba/F3 (Figure 2A; upper panel) leads to enhanced cell migration, increased membrane ruffling/formation of lamellipodia and filopodia, formation of pseudopods, and decreased ability to retract uropods as assessed by time-lapse video microscopy (TLVM) (Salgia et al., 1999b). STI 571 treatment of these cells led to decreased cell motility with decreased migration/ruffling and reduced active protruding structures within 6 h (Figure 2A; lower panel).
The cell motility of small cell lung cancer cells was different than the BCR/ABL expressing Ba/F3 hematopoietic cells. NCI-H69 SCLC cells (Figure 2B; upper panel) tended to move together as a cluster and had membrane ruffling, characterized by membrane ‘blebs’. Also, single SCLC cells tended to combine with the cluster as visualized by TLVM. The clustered cells also moved as a combined entity rather than reflecting single cell movement, which is classic for hematopoietic cells. NCI-H69 cells did not have any membrane ruffling/blebbing or any migrational changes, within 6 h of treatment with 5 μM STI 571 (Figure 2B; lower panel). The cell motility of NCI-H82 and NCI-H249 was not affected by treatment with 5 μM STI 571 (data not shown).
Cell cycle analysis
Cell cycle distribution of STI 571-treated viable SCLC cells was analysed by flow cytometry (Figure 3). There was accumulation of cells in G2/M in NCI-H69 cells, but not in NCI-H249 cells (22% in NCI-H69 versus 5.2% in NCI-H249), after 48 h of treatment with STI 571 (5 μM). No obvious G1/S arrest was identified.
Reactive oxygen species
We assessed the endogenous levels of reactive oxygen species (ROS) in SCLC cell lines, with and without treatment with STI 571. The relative ROS levels in SCLC cell lines were measured with the fluorochrome 2′,7′-dichloro-fluorescin-diacetate (Figure 4). The relative ROS levels were decreased in response to STI 571 at 5 μM, in the responsive NCI-H69 cell line by approximately 60% and not the unresponsive NCI-H249 cell line.
STI 571 can inhibit phosphorylation of c-Kit in responsive SCLC cell lines
Previously, it had been shown that the c-Kit/SCF is an important viability growth factor autocrine loop in SCLC (Krystal et al., 1996). Utilizing the NCI-H69 cell line and treating with anti-c-Kit blocking antibody at 100 μg/ml for 48 h (mimicking the conditions detailed above for STI 571), we found that there was growth inhibition by 38% as compared to controls. This further led us to study the role of c-Kit in STI 571 inhibition of SCLC cell lines.
The SCLC cell lines (NCI-H69, NCI-H146, NCI-H209) had detectable c-Kit receptor at 145 kDA by Western blot analysis (Figure 5A). MO7e megakaryocytic cell line, a hematopoietic cell line previously shown to express abundant amounts of c-Kit receptor, had an easily detectable signal for c-Kit and is presented as a control. The SCLC cell lines (NCI-H249 and NCI-H82) and a NSCLC cell line (NCI-H661) did not have detectable amounts of c-Kit protein. In all the SCLC cell lines tested, there was no detectable expression of PDGF receptor (data not shown).
Small cell lung cancer cell lines (NCI-H69, NCI-H146 and NCI-H209) with detectable c-Kit receptor underwent tyrosine phosphorylation in response to stem cell factor (SCF). Multiple tyrosine-phosphorylated bands were appreciated in response to SCF stimulation at 50 ng/ml with a phosphorylated band at 145 kDa consistent with c-Kit receptor (Figure 5B).
Immunoprecipitation with anti-c-Kit antibody and Western blot analysis with anti-phosphotyrosine antibody was performed for lysates of small cell lung cancer cells treated with SCF (50 ng/ml) and 0.1–10 μM STI 571 (Figure 6A, upper panel). There was reduction of c-Kit phosphorylation at 1–10 μM STI 571 in the small cell cancer cell line NCI-H69. As a control, the bottom panel shows relatively similar concentrations of c-Kit immunoprecipitated, as detected by anti-c-Kit immunoblot.
In vitro kinase assays were performed for STI 571 treated (5 μM) cells (Figure 6B). There was approximately 50% reduction of in vitro kinase activity in response to STI 571. It should be noted that in vitro autophosphorylation kinase activity was not increased in these cells in response to SCF.
STI 571 effects downstream signaling to Akt by c-Kit
Akt phosphorylation in response to SCF in SCLC cell lines (NCI-H69 and NCI-H209) was investigated. The ability of STI 571 to block Akt phosphorylation was also studied. Figure 7 shows that Akt was serine phosphorylated in response to SCF stimulation of c-Kit, and STI 571 inhibited this phosphorylation.
The studies in this report have characterized another mechanism of growth inhibition of small cell lung cancer cells by interrupting an autocrine growth loop and the downstream effects of STI 571 on the receptor tyrosine kinase, c-Kit.
STI 571 was initially designed based on the structure of the ATP binding site, and belongs to the 2-phenylaminoprimidine class (Buchdunger et al., 1996). STI 571 was shown to inhibit Abl tyrosine kinases (including c-Abl, v-Abl, BCR/ABL, and TEL/ABL) with an IC50 of approximately 0.1–0.25 μM (Carroll et al., 1997; Druker et al., 1996; Sawyers and Druker, 1999). The inhibition of the Abelson tyrosine kinase makes it an attractive target for chronic myelogenous leukemia where the Abl kinase is activated by a 9 : 22 chromosomal translocation (Sattler and Salgia, 1997). In Ph+ cell lines (K562, BV173, MO7e with BCR/ABL, BaF3 with BCR/ABL, 32Dcl3 with BCR/ABL) cytotoxicity assays (MTT and trypan blue viable cell count) showed cell death or growth inhibition between 1–10 μM, with STI 571, and cytotoxicity was specific for BCR/ABL containing cells (Sawyers and Druker, 1999).
Although Abl is not activated in SCLC, another tyrosine kinase autocrine loop, stem cell factor and its receptor c-Kit is present and functional. Three of five SCLC cell lines tested (NCI-H69, NCI-H146, and NCI-H209) showed decreased viability with an IC50 of approximately 1 μM. The in vitro concentration of STI 571 needed to inhibit the growth of Ph+ hematopoietic cells was also approximately 1 μM. We have studied viability because of the varied role of tyrosine kinases in the biology for tumor cells, and the molecular events affected by their inhibition may be quite different. The antiproliferative effect of tyrosine kinase inhibitor results in inhibition of tumor growth but may not necessarily effect tumor survival (Druker and Lydon. 2000).
STI 571 has been studied extensively in hematopoietic cells. We have further studied the effects of STI 571 on hematopoietic cells by demonstrating that cell motility of BCR/ABL cells (usually characterized by enhanced cell migration, increased membrane ruffling/formation of lamellipodia, formation of filopodia, decreased ability to retract uropods) (Salgia et al., 1997) was inhibited by STI 571. We have previously shown that the cell motility of CML cells is mainly mediated by Rac and P13K (Salgia et al., 1998). It can be postulated from the data presented here that BCR/ABL tyrosine kinase activity is probably the most important signal for CML cell motility. In contrast to CML cells, the cell motility of SCLC cells was detected mainly as cell cluster movement as well as individual cell membrane ruffling/blebbing. In the STI 571 responsive SCLC cell lines, at similar concentrations used as that of BCR/ABL hematopoietic cell lines, there was inhibition of cell motility within 6 h.
ROS are formed in response to growth factors such as GM-CSF, IL-3, SCF, and TPO in hematopoietic cells such as Mo7e and TF-1 (Sattler et al., 1999b). The activation of ROS is not only linked to activating kinases but also inhibiting phosphatases. SCLC cell lines that are responsive to STI 571 (such as NCI-H69) had decreased formation of ROS by at least 60% within 24–48 h of treatment with STI 571. We have specifically implicated c-Kit phosphorylation as a target of STI 571 in this study. However, it is possible that the reduction of ROS species in SCLC by STI 571 is secondary to the loss of crucial balances between various kinases and phosphatases in the cell.
The inhibition of viability of small cell lung cancer cells by STI 571 appears to be related to the presence of c-Kit receptors. The three cell lines with detectable c-Kit receptor by Western blot had their viability decreased by STI 571 while those cell lines with no detectable c-Kit receptors are not impeded. It is noted that by Western blot analysis, NCI-H146 cell had detectable c-Kit protein with a small band at approximately 145 kDa recognized by the antibody. This band was phosphorylated in response to SCF although not as much as the other bands in NCI-H69 and NCI-H209 cell lines. This is in contrast to the published data (Plummer et al., 1993) for NCI-H146, in that there was no appreciable c-Kit mRNA detected by Northern blot analysis and by flow cytometric analysis of biotinylated SCF binding. The reasons for the difference could be that by immunoblotting we are able to detect c-Kit receptor levels, and certainly we can state that upon stimulation with SCF, there are several new tyrosine phosphorylated bands which are recognized in c-Kit protein expressing cell lines. There is agreement between the findings of c-Kit and stem cell factor between Krystal's study and our study in the other small cell lung cancer lines studied (Krystal et al., 1996; Plummer et al., 1993). Finally, there is a possibility that STI 571 may not be only inhibiting c-Kit but also other tyrosine kinases as yet unidentified.
The usefulness of STI 571 in SCLC reflects the growing field of utilization of tyrosine kinase inhibitors in hematologic malignancies and solid tumors. As recently reviewed, there are many tyrosine kinase inhibitor compounds in pre-clinical and clinical studies (Druker and Lydon, 2000). Tyrosine kinase inhibitors would be expected to target the various hyperproliferative signals reflected by the potent tyrosine kinases. Potentially, PDGF-receptor, EGF-receptor, Src, c-Met, and KDR are all good targets for inhibiting tumor growth in various solid tumors. As an example, as has been shown recently, EGF-receptor can be overexpressed and be required for growth signalling in non-small cell lung cancer. Utilizing the orally administered EGF-receptor inhibitor ZD1839 (‘Iressa’ AstraZeneca, UK), in a phase I dose-escalation trial, there have been reported antitumor responses among 16 non-small cell lung cancer patients (two patients with partial response, two patients with significant response, and two patients with stable disease) (Ferry et al., 2000).
Our data also shows that STI 571 blocked the phosphorylation of Akt, which is downstream from c-Kit. SCF has very minimal effects on the growth of hematopoietic progenitors; however, it appears to be an important growth factor for SCLC cells. As shown by Krystal et al. (1996), when a kinase defective c-Kit (frame shift mutation in extracellular domain of c-Kit) is introduced into c-Kit/SCF expressing cell line, there is growth depression. It would also be of interest to determine the effects of this drug on other solid tumors such as non-small cell lung cancer, melanoma and GI stromal tumors, all of which can express activated or mutated c-Kit (DiPaola et al., 1997).
Materials and methods
Cell lines and cell culture
The non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines were obtained from the American Type Culture Collection (Rockville, MD, USA). The SCLC cell lines (NCI-H69, NCI-H209, NCI-H146, NCI-H249, and NCI-H82) cells were maintained in RPMI 1640 media (Mediatech), 10% (v/v) fetal calf serum, and 1% (v/v) penicillin-strepomycin (Salgia et al., 1999a). All cell lines were then incubated at 37°C with 5% CO2. K562 cells and BLIN-1 cells were also obtained from the ATCC and cultured as previously described (Sattler et al., 1999a). The megakaryocytic cell line Mo7e was cultured as described (Sattler et al., 1999a). BCR/ABL expressing Ba/F3 cells (BaF3.p210) were generated and maintained as previously described (Salgia et al., 1999b). The cell lines were harvested during log phase growth, and cells were exposed to various concentrations of STI 571 (Novartis, Basil, Switzerland) for 3–96 h.
The anti-phosphotyrosine monoclonal antibody, mAb #4G10, was a generous gift from Dr Brian Druker, University of Oregon Health Science Center, Portland, Oregon, USA, and was used at 1 to 2500 dilution for an immunoblot. The anti c-Kit, Akt, phospho-Akt, PI3 kinase antibodies were obtained from Santa Cruz Biotechnology, Inc. (Santa Cruz, CA, USA), and utilized as previously described (Sattler et al., 1997). For blocking antibody studies, anti-c-Kit monoclonal antibody, mAb #44.2 (clone Ab2), was a generous gift from Dr Atul Tandon, NeoMarkers, Union City, CA, USA. Anti-c-Kit monoclonal antibody was used at 100 μg/ml, and incubated for 48 h with NCI-H69 cells in their culture media, and viability measured.
Analysis of reactive oxygen species in small cell lung cancer
A total of 106 cells were treated with DMSO or STI 571 (5 μM) were incubated with 5 μM DCF-DA (2′,7′-dichloroflurorescein-diacetate; Acros Organics, Pittsburgh, PA, USA) for 5 min at 37°C and subsequently washed twice in cold Dulbecco's phosphate buffered saline (PBS) before analysis using a Coulter Epics XL flow cytometer (Coulter Corp., Miami, FL, USA). DCF-DA is a cell permeable dye commonly used to monitor intracellular changes in ROS. This compound becomes fluorescent when oxidized by either H2O2 or super oxide. The fluorescence of oxidized DCF was measured with an excitation wavelength of 480 nm and an emission wavelength of 525 nm (Sattler et al., 1999b).
Cell cycle analysis
SCLC cells were treated at 37°C with either DMSO or STI 571 at concentration of 5 μM and analysed after propidium iodide staining using standard methods. In brief, 0.5×106 cells per sample were washed once in cold Dulbecco's PBS and resuspended in 500 μl staining solution containing 50 mg/ml propidium iodide, 0.1% (V/V) NP-40, and 0.1% (weight/volume) sodium citrate. Single cell suspensions were obtained by vigorous pipetting, and cells were incubated at 4°C in the dark for 15 min and then analysed by flow cytometry (Sattler et al., 1999b).
Cells were cultured on uncoated plastic tissue culture plates (35×10 mm plates, Beckton-Dickinson Labware) in a temperature-controlled chamber at 37°C and their previously described media. The cells were examined by videomicroscopy utilizing Olympus IX70 inverted microscope, omega temperature controlled device, Optronics Engineering DEI-750 video camera, Olympus OEV142 TV and Panasonic AG6740 time lapse S-VHS video recorder continuously. The digital video images were captured and printed with a Sony UP5600MD Color Video Printer (Salgia et al., 1999b).
Preparation of cell lysates and immunoblotting
Cell lines were lysed in lysis buffer as previously described (Salgia et al., 1995). Cell lysates were separated by 7.5% SDS–PAGE under reducing conditions, electrophoretically transferred to immobilon polyvinylidene diflouride (Millipore, Bedford, MA, USA) and processed for immunoblotting using established methods with enhanced chemiluminescense technique (Amersham Corp.). Also, immunoprecipitations were performed according to standard procedures and immonoblotting thereafter. In vitro kinase assays were performed as described previously (Sattler et al., 1997).
Buchdunger E, Zimmermann J, Mett H, Meyer T, Muller M, Druker BJ and Lydon NB. . 1996 Cancer Res. 56: 100–104.
Carroll M, Ohno-Jones S, Tamura S, Buchdunger E, Zimmermann J, Lydon NB, Gilliland DG and Druker BJ. . 1997 Blood 90: 4947–4952.
Chaudhry A, Carrasquillo JA, Avis IL, Shuke N, Reynolds JC, Bartholomew R, Larson SM, Cuttitta F, Johnson BE and Mulshine JL. . 1999 Clin. Cancer Res. 5: 3385–3393.
Chute JP, Chen T, Feigal E, Simon R and Johnson BE. . 1999 J. Clin. Oncol. 17: 1794–1801.
DiPaola RS, Kuczynski WI, Onodera K, Ratajczak MZ, Hijiya N, Moore J and Gewirtz AM. . 1997 Cancer Gene Ther. 4: 176–182.
Druker BJ and Lydon NB. . 2000 J. Clin. Invest. 105: 3–7.
Druker BJ, Talpaz M, Resta D, Peng B, Buchdunger E, Ford J and Sawyers C. . 1999 Blood 94: 368a.
Druker BJ, Tamura S, Buchdunger E, Ohno S, Segal GM, Fanning S, Zimmermann J and Lydon NB. . 1996 Nat. Med. 2: 561–566.
Ferry D, Hammond L, Ranson M, Kris M, Miller V, Murray P, Tullo A, Feyereislova A, Averbuch S and Rowinsky E. . 2000 Proc. ASCO. 19: 3a.
Hibi K, Takahashi T, Sekido Y, Ueda R, Hida T, Ariyoshi Y and Takagi H. . 1991 Oncogene 6: 2291–2296.
Johnson BE and Kelley MJ. . 1995 Lung Cancer 12: S5–S16.
Krystal GW, Hines SJ and Organ CP. . 1996 Cancer Res. 56: 370–376.
Plummer HD, Catlett J, Leftwich J, Armstrong B, Carlson P, Huff T and Krystal G. . 1993 Cancer Res. 53: 4337–4342.
Salgia R, Li JL, Ewaniuk DS, Pear W, Pisick E, Burky SA, Ernst T, Sattler M, Chen LB and Griffin JD. . 1997 J. Clin. Invest. 100: 46–57.
Salgia R, Li JL, Ewaniuk DS, Wang YB, Sattler M, Chen WC, Richards W, Pisick E, Shapiro GI, Rollins BJ, Chen LB, Griffin JD and Sugarbaker DJ. . 1999a Oncogene 18: 67–77.
Salgia R, Li JL, Lo SH, Brunkhorst B, Kansas GS, Sobhany ES, Sun Y, Pisick E, Hallek M, Ernst T, Tantravahi R, Chen LB and Griffin JD. . 1995 J. Biol. Chem. 270: 5039–5047.
Salgia R, Lin J, Narsimhan R, Chen W, Mach N, Dranoff G, Sattler M and Griffin J. . 1998 Blood 92: 487a.
Salgia R, Quackenbush E, Lin J, Souchkova N, Sattler M, Ewaniuk DS, Klucher KM, Daley GQ, Kraeft SK, Sackstein R, Alyea EP, von Andrian UH, Chen LB, Gutierrez-Ramos JC, Pendergast AM and Griffin JD. . 1999b Blood 94: 4233–4246.
Sattler M and Salgia R. . 1997 Cytokine Growth Factor Rev. 8: 63–79.
Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV and Griffin JD. . 1997 J. Biol. Chem. 272: 10248–10253.
Sattler M, Verma S, Byrne CH, Shrikhande G, Winkler T, Algate PA, Rohrschneider LR and Griffin JD. . 1999a Mol. Cell. Biol. 19: 7473–7480.
Sattler M, Winkler T, Verma S, Byrne CH, Shrikhande G, Salgia R and Griffin JD. . 1999b Blood 93: 2928–2935.
Sawyers CL and Druker B. . 1999 Cancer. J. Sci. Am. 5: 63–69.
This work was supported by NIH grant CA75348-03 and Lowe's Center for Thoracic Oncology (R. Salgia), and Leukemia Research Foundation Fellowship (M. Sattler).
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Cite this article
Wang, WL., Healy, M., Sattler, M. et al. Growth inhibition and modulation of kinase pathways of small cell lung cancer cell lines by the novel tyrosine kinase inhibitor STI 571. Oncogene 19, 3521–3528 (2000). https://doi.org/10.1038/sj.onc.1203698
- small cell lung cancer
- c-Kit and stem cell factor
- STI 571
- signal transduction in lung cancer
- cell motility
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