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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
1 Division of Hematology-Oncology, Department of Medicine, David Geffen School of Medicine, University of California at Los Angeles and Jonsson Comprehensive Cancer Center, Los Angeles, California; 2 Department of Gynecologic Surgery, Mayo Clinic, Rochester, Minnesota; 3 Department of Obstetrics and Gynecology, Klinikum Grosshadern, Ludwig Maximilians Universität München, Munich, Germany; 4 GlaxoSmithKline, Research Triangle Park, North Carolina; 5 Piedmont Research Center, Morrisville, North Carolina; and 6 GlaxoSmithKline, Collegeville, Pennsylvania
Requests for reprints: Gottfried E. Konecny, Division of Hematology-Oncology, University of California at Los Angeles, 12-145 Factor Building, 10945 Le Conte Avenue, Los Angeles, CA 90095-1678. E-mail: gkonecny{at}ucla.edu.
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Introduction |
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20% of human breast cancers and is associated with an aggressive form of the disease with significantly shortened disease-free survival and overall survival (10). It has been suggested that HER-2 may play an important role in the oncogenic activity of EGFR, because preclinical experiments have shown that HER-2 and EGFR act synergistically to transform NIH3T3 cells (11). Being the most common heterodimerization partner of EGFR (6), HER-2 potentiates EGFR signaling in trans by enhancing the binding affinity of its ligand EGF (12), reducing its degradation (13), and predisposing the receptor to recycling (14). In turn, it has been shown that EGF-induced stimulation of EGFR leads to activation of HER-2 by transduction through heterodimerization (2, 15), and recent studies have shown that EGFR-specific inhibitors can reduce HER-2 signaling and growth of breast cancer cells that express high levels of HER-2 (16–18). Thus, combined inhibition of both EGFR and HER-2 may be more efficacious than targeting either one of them alone.
One successful antireceptor strategy has been the development of trastuzumab, a humanized monoclonal antibody, which targets the extracellular domain of HER-2 (19, 20). An alternative antireceptor strategy has been the development of small-molecule inhibitors that compete with ATP for the ATP-binding domain in the intracellular portion of receptor tyrosine kinases. Recently, agents have been developed that simultaneously inhibit both EGFR and HER-2 epithelial growth factor receptors (21). Lapatinib is such a synthetic small-molecule inhibitor of the HER-2 and EGFR tyrosine kinases (22). This compound is a potent ATP-competitive inhibitor in cell-free biochemical kinase assays inhibiting the recombinant EGFR and HER-2 tyrosine kinases by 50% (IC50) at concentrations of 10.8 and 9.3 nmol/L, respectively (22). Lapatinib is a reversible inhibitor with estimated dissociation constant (Ki) values of 3 and 13 nmol/L for EGFR and HER-2, respectively (23). In cell-based assays, lapatinib inhibits the growth of HER-2-overexpressing BT474 breast cancer cells at comparably low concentrations (IC50, 100 nmol/L; ref. 22). However, 30- to 40-fold higher concentrations are necessary to inhibit MCF-7 and T47D human breast cancer cells, which both express normal levels of EGFR and HER-2 (22). Thus, evaluation of additional breast cancer cell lines each expressing different levels of EGFR and HER-2 may provide more comprehensive information on the potential utility of a dual kinase inhibitor in intact breast cancer cells.
Because the in vitro studies were carried out for short-term periods (7 days), we further evaluated the long-term effect of lapatinib in vivo. BT474 human breast carcinoma xenografts, which are tumorigenic in athymic mice, served as the tumor target for the in vivo studies.
Because lapatinib inhibits the tyrosine kinase activity of HER-2 itself in addition to that of its coreceptor EGFR, this small-molecule inhibitor might increase the activity of trastuzumab or show activity in cells with acquired resistance to the HER-2 antibody trastuzumab. To address this possibility, we characterized the effects of combinations of lapatinib and trastuzumab in HER-2-overexpressing breast cancer cells using the median effect/combination index (CI) isobologram method for multiple drug effect analysis (24). Moreover, we assessed the activity of lapatinib against cells selected for long-term outgrowth in trastuzumab-containing medium. Such trastuzumab-conditioned HER-2-overexpressing breast cancer cells were used to study the activity of lapatinib in cells with acquired resistance to the HER-2 antibody trastuzumab.
Finally, we sought to identify downstream biomarkers associated with response to lapatinib. This was accomplished by measuring EGFR and HER-2 receptor expression and assaying the phosphorylation status of EGFR, HER-2, and signaling intermediates, such as Raf, AKT, and extracellular signal-regulated kinase (ERK), in each of the cell lines both before and after exposure to lapatinib.
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Materials and Methods |
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Quantitation of HER-2 and EGFR expression. HER-2 and EGFR protein content was measured with a commercially available quantitative ELISA (Oncogene Research Products/Calbiochem, San Diego, CA, and R&D Systems, Minneapolis, MN, respectively) according to the manufacturer's instructions. Cell lysates were prepared as described previously (26), and HER-2 and EGFR protein levels were given in nanogram per milligram of total protein.
Proliferation assays. Cells were plated into 24-well plates at a density of 2 x 105 to 5 x 105 and grown in cell line–specific medium without or with increasing concentrations of lapatinib (ranging between 0.008 and 10 µmol/L). Cells were harvested by trypsinization on day 7 and counted using a particle counter (Z1, Beckman Coulter, Inc., Fullerton, CA). Growth inhibition was calculated as a percentage of the untreated controls. Experiments were done twice to thrice in duplicate for each cell line. The log of the fractional growth inhibition was then plotted against the log of the drug concentration, and the IC50s were interpolated from the resulting linear regression curve fit (Calcusyn, Biosoft, Ferguson, MO). Comparisons of IC50s between cell lines were done using the Student's t test.
Cell cycle analysis. Cells were plated in six-well tissue culture dishes and treated with vehicle (0.1% DMSO) or lapatinib at the concentrations indicated for 24 hours. Cells were then trypsinized, collected, and washed in PBS. Cells were subsequently fixed in 70% ethanol, incubated HCl/Triton X-100, washed, and stained with propidium iodide. Samples were analyzed on the FacSort (Becton Dickinson, San Jose, CA). DNA content was estimated by gating histograms generated with the FL2-area variable.
Analysis of long-term activity of lapatinib against HER-2-overexpressing breast carcinoma xenografts in vivo. C.B-17 severe combined immunodeficient female mice (4-6 weeks old) were purchased from Charles River Laboratories (Wilmington, MA). The research complied with national legislation and with company policy on the Care and Use of Animals and with related codes of practice. BT474 human tumor xenografts were initiated by implantation of tumor fragments (20-100 mg) from established tumors. Tumor size was estimated using the formula: Length x Width2 / 2 = Tumor volume (mm3). Treatment began when tumors were palpable and 3 to 5 mm in diameter. Experimental compounds were given p.o. twice daily for 77 days in a vehicle of 0.5% hydroxypropylmethylcellulose/0.1% Tween 80. The groups treated with vehicle control contained 8 mice, and the group treated with 75 mg/kg over 77 days contained 16 mice. Statistical significance of the differences was analyzed by single-factor ANOVA of the log-transformed tumor volume data.
Immunoprecipitation and Western blots. Following treatment with lapatinib as indicated, cells were washed in PBS and lysed at 4°C in lysis buffer. Insoluble material was cleared by centrifugation at 10,000 x g for 10 minutes. Protein was quantitated using BCA (Pierce, Rockford, IL), resolved by SDS-PAGE, and transferred to nitrocellulose membranes (Invitrogen Life Technologies). HER-2, EGFR, AKT, and ERK expression were detected by monoclonal anti-HER-2 (Ab-3, Calbiochem), anti-EGFR antibodies (Pharmingen, San Diego, CA), polyclonal anti-AKT (AKT1, AKT2, and AKT3 protein kinases) and anti-ERK1/2 (p44/42 mitogen-activated protein kinase) antibodies (Cell Signaling Technology, Beverly, MA), respectively. pAKT and pERK were detected by polyclonal anti-pAKT (Ser473) and anti-pERK (Tyr202/Tyr204) antibodies (Cell Signaling Technology). pRaf was detected by a polyclonal anti-pRaf-1 (Ser338) antibody (Upstate, Charlottesville, VA). Tyrosine phosphorylation of HER-2 and EGFR was analyzed as follows. Immunoprecipitations were done by allowing 250 µg protein lysate to incubate with 3 µg monoclonal anti-HER-2 (Ab-3) or anti-EGFR antibody (Ab-1, Calbiochem) and protein A/G-agarose (Santa Cruz Biotechnology, Santa Cruz, CA) at 4°C overnight with gentle agitation. The immunoprecipitates were washed thrice in lysis buffer and then denatured in Laemmli buffer before SDS-PAGE. Immunoblotting was done using a monoclonal anti-phosphotyrosine antibody (Upstate). Detection for concentration- and time-dependent experiments were done using enhanced chemiluminescence (ECL; Amersham Biosciences, Piscataway, NJ) or Dura system (Pierce). Densitometry of the resulting Western blots was done using the ImageQuant software (Amersham Biosciences). Detection in all other experiments was done using ECL Plus chemifluorescent reagent (Amersham Biosciences), and densitometry of the resulting Western blots was done using the chemifluorescence method by Typhoon 9400 (Amersham Biosciences). Results were controlled for equal loading and exposure time by comparison with relative tubulin content. Correlations between IC50s and the percent reduction of baseline phosphorylation levels were done by calculating the Spearman's rho correlation coefficient.
Multiple drug effect analysis. Aliquots of 3 x 103 to 5 x 103 SK-BR-3, BT474, MDA-MB-361, and MDA-MB-453 cells were plated in 96-well microdilution plates. Following cell adherence (24 hours), experimental medium containing either control medium, trastuzumab, lapatinib, or the combination (trastuzumab plus lapatinib) were added to appropriate wells in duplicate, and serial 2-fold dilutions were done to span clinically relevant concentration ranges for the dose-effect analysis for trastuzumab and lapatinib or drug combination. Multiple drug effect analysis was done as described previously (24, 27). CI values were derived from variables of the median effect plots and statistical tests were applied (unpaired, two-tailed Student's t test) to determine whether the mean CI values at multiple effect levels were significantly different from CI = 1. In this analysis, synergy is defined as CI values significantly lower than 1.0, antagonism as CI values significantly higher than 1.0, and additivity as CI values equal to 1.0.
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20 µg/mL and peak plasma concentrations of 185 µg/mL (33). Trastuzumab significantly inhibited growth of HER-2-overexpressing BT474 (P < 0.001), SK-BR-3 (P < 0.001), and MDA-MB-361 cells (P < 0.001) when compared with untreated controls but much less than lapatinib (Fig. 4A). Trastuzumab showed no growth-inhibitory effect on the trastuzumab-conditioned sublines BT474/mAbHER-2 (P = 0.34) and MDA-MB-361/mAbHER-2 (P = 0.35) when compared with untreated controls and showed less growth inhibition in SK-BR-3/mAbHER-2 when compared with untreated controls (P = 0.03; Fig. 4B). In contrast, lapatinib retained significant activity in the trastuzumab-conditioned sublines BT474/mAbHER-2 (P < 0.001), SK-BR-3/mAbHER-2 (P < 0.001), and MDA-MB-361/mAbHER-2 (P < 0.001) when compared with untreated controls (Fig. 4B).
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Effects of lapatinib on HER-2 and EGFR signaling. Exposure of SK-BR-3 and BT474 human breast cancer cells to lapatinib resulted in a dose- and time-dependent reduction of phosphorylation of EGFR, HER-2, AKT, and ERK (Fig. 5A and B). We next examined the effect of lapatinib on HER-2 and EGFR receptor phosphorylation both with and without prior exposure to heregulin ß1 (Fig. 5C and D). Heregulin ß1 is a growth factor ligand cloned based on its ability to induce tyrosine phosphorylation of HER-2 through the formation of HER-2/HER-3 and/or HER-2/HER-4 heterodimeric complexes (1, 4). In HER-2-overexpressing breast cancer cell lines (SKBR3 and UACC-893), which constitutively express an activated HER-2 tyrosine kinase, heregulin ß1 does not further increase HER-2 phosphorylation, indicating that this receptor is being maximally activated in these cell lines at baseline (35). The data indicate that heregulin ß1 does not interfere with the ability of lapatinib to reduce HER-2 phosphorylation in either cell lines with constitutive HER-2 tyrosine phosphorylation or cell lines with increased HER-2 tyrosine phosphorylation following exposure to heregulin ß1 (Fig. 5C). We next studied the ability of lapatinib to block HER-2 and EGFR receptor phosphorylation both with and without prior exposure to transforming growth factor-
(TGF-), which is a native ligand of the EGFR. As expected, treatment with TGF- strongly stimulated EGFR phosphorylation (Fig. 5D), but lapatinib consistently decreased EGFR phosphorylation back to basal levels. Importantly, however, basal EGFR phosphorylation following exposure to TGF- and subsequent treatment with lapatinib were higher compared with EGFR phosphorylation levels following lapatinib treatment without exposure to TGF-. These findings indicate that lapatinib did not completely inhibit phosphorylation of EGFR following stimulation with TGF-. On ligand binding, the EGFR can form heterodimeric complexes with neighboring HER-2 receptors (36, 37) and transactivate HER-2. As expected, TGF- induced HER-2 tyrosine phosphorylation in breast cancer cells without constitutive HER-2 phosphorylation (Fig. 5C). Consistent with heregulin ß1 data, TGF--induced transactivation of HER-2 did not reverse the inhibitory effects of lapatinib on the HER-2 tyrosine kinase (Fig. 5C).
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Discussion |
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The association between HER-2 overexpression and increased response to lapatinib was substantiated using a panel of paired control- and HER-2-transfected cells. This pairing of isogenic parent/daughter cells allows us to isolate HER-2 expression as a variable and directly assess the biological consequences of its overexpression on lapatinib response. These data confirm that breast cancer cells with HER-2 overexpression are significantly more sensitive to lapatinib compared with control cell lines in vitro. Moreover, our studies indicate that inhibition of tyrosine phosphorylation of HER-2, Raf, AKT, and ERK were also significantly associated with in vitro response to lapatinib, suggesting that these may also be useful markers to predict response to this molecule. This will, however, require confirmation in prospective clinical trials.
To further validate the activity of lapatinib in HER-2-overexpressing breast cancer cells, parallel in vitro studies were conducted measuring the fragmentation of genomic DNA into sub-2N DNA (sub-G1 DNA), generally considered a hallmark of apoptosis, following treatment with lapatinib at concentrations of 0.1 and 0.5 µmol/L. Our results are consistent with the findings of previous studies that have shown that HER-2-overexpressing cells undergo apoptosis following treatment with lapatinib at higher concentrations of 1 and 10 µmol/L (22). We further showed that lapatinib given over 21 days at doses of 75 mg/kg twice daily nearly completely inhibits the growth of HER-2-overexpressing human breast cancer cells in vivo using the BT474 xenograft model. Moreover, our results of long-term in vivo treatment indicate that extended dosing of lapatinib over 77 days results in statistically significant suppression of tumor growth over the entire duration of the experiment.
Although it may be tempting to establish a parallel between agents inhibiting EGFR and agents inhibiting HER-2, the biology of EGFR is quite different from HER-2. EGFR is commonly expressed in breast cancer (40), but higher levels of expression per se do not define "EGFR-driven" tumors, as the effect of EGFR inhibitors is not well correlated with the levels of EGFR expression (41) and EGFR levels do not correlate with evidence of EGFR activation (42). However, in addition to its function as an individual receptor, EGFR may play an important role as a coreceptor for HER-2 (43). The cooperation that exists between EGFR and HER-2 provides a sound rationale to target EGFR particularly when HER-2 is overexpressed. The pure EGFR tyrosine kinase inhibitor gefitinib inhibits the growth of HER-2-overexpressing BT474, SKBR-3, and MDA-361 human breast cancer cells at low micromolar drug concentrations (17, 18). These effects may be due to inhibition in the transactivation of EGFR (rather than direct inhibition of HER-2). The cooperation that exists between EGFR and HER-2 may, however, also limit the success of agents that target individual receptors. Preclinical studies have shown that the antiproliferative activity of a HER-2 antibody can be decreased by the presence of ligand for the EGFR (44). In return, the activity of this HER-2 antibody can be restored by a tyrosine kinase inhibitor with dual activity against EGFR and HER-2 (44). Thus, simultaneous inhibition of different receptors may constitute a superior way of correcting a dysregulated signaling network.
To determine how best to use lapatinib either as a single agent or in combination with trastuzumab, we conducted a series of in vitro studies to evaluate its inhibitory effects in combination with trastuzumab. These preclinical studies have shown significantly enhanced activity when trastuzumab is combined with lapatinib in HER-2-positive breast cancer cells. At present, reasons for this synergy are unclear. A detailed analysis of HER-2 receptor phosphorylation following short treatment of SK-BR-3 and BT474 cells with trastuzumab, however, reveals a moderate increase of HER-2 tyrosine phosphorylation by trastuzumab treatment (45). Such an initial stimulatory effect of trastuzumab on HER-2 phosphorylation is in contrast to the pronounced immediate inhibitory effect of lapatinib on HER-2 phosphorylation as shown above in our studies (Fig. 5B). Thus, it may be possible that trastuzumab may initially sensitize cells to treatment with lapatinib. Furthermore, a recent study has indicated that combining lapatinib with trastuzumab enhances apoptosis in HER-2-overexpressing breast cancer cells (46). Regardless of the mechanism(s) of in vitro synergy, the current data indicate a consistent synergistic interaction between trastuzumab and lapatinib across all cell lines tested and clearly support further clinical evaluation of these agents in a combined regimen (47). Such strategies in the clinical setting could add more effective inhibition of the receptor tyrosine kinase to an additional important mechanism of action of trastuzumab thought to occur through immune effector cells (48).
In the current study, we were able to show activity of lapatinib against cells selected for long-term growth in trastuzumab-containing medium. These findings suggest non-cross-resistance between these two HER-2-directed agents and underscore the importance of current clinical trials evaluating lapatinib in trastuzumab-refractory breast cancer (49).
Taken together, our findings provide a rationale for clinical trials of lapatinib as a single agent or in combination with trastuzumab in HER-2-overexpressing breast cancer and suggest the potential of clinical activity in patients with resistance to trastuzumab.
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Acknowledgments |
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Received 4/11/05. Revised 11/11/05. Accepted 11/17/05.
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H.-P. Kim, S.-W. Han, S.-H. Kim, S.-A. Im, D.-Y. Oh, Y.-J. Bang, and T.-Y. Kim Combined lapatinib and cetuximab enhance cytotoxicity against gefitinib-resistant lung cancer cells Mol. Cancer Ther., March 1, 2008; 7(3): 607 - 615. [Abstract] [Full Text] [PDF]
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K. M. Aird, X. Ding, A. Baras, J. Wei, M. A. Morse, T. Clay, H. K. Lyerly, and G. R. Devi Trastuzumab signaling in ErbB2-overexpressing inflammatory breast cancer correlates with X-linked inhibitor of apoptosis protein expression Mol. Cancer Ther., January 1, 2008; 7(1): 38 - 47. [Abstract] [Full Text] [PDF]
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O. Rixe and T. Fojo Is Cell Death a Critical End Point for Anticancer Therapies or Is Cytostasis Sufficient? Clin. Cancer Res., December 15, 2007; 13(24): 7280 - 7287. [Abstract] [Full Text] [PDF]
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J. Krol, R. E. Francis, A. Albergaria, A. Sunters, A. Polychronis, R. C. Coombes, and E. W.-F. Lam The transcription factor FOXO3a is a crucial cellular target of gefitinib (Iressa) in breast cancer cells Mol. Cancer Ther., December 1, 2007; 6(12): 3169 - 3179. [Abstract] [Full Text] [PDF]
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T. Barrett, Y. Koyama, Y. Hama, G. Ravizzini, I. S. Shin, B.-S. Jang, C. H. Paik, Y. Urano, P. L. Choyke, and H. Kobayashi In vivo Diagnosis of Epidermal Growth Factor Receptor Expression using Molecular Imaging with a Cocktail of Optically Labeled Monoclonal Antibodies Clin. Cancer Res., November 15, 2007; 13(22): 6639 - 6648. [Abstract] [Full Text] [PDF]
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J. P. Jani, R. S. Finn, M. Campbell, K. G. Coleman, R. D. Connell, N. Currier, E. O. Emerson, E. Floyd, S. Harriman, J. C. Kath, et al. Discovery and Pharmacologic Characterization of CP-724,714, a Selective ErbB2 Tyrosine Kinase Inhibitor Cancer Res., October 15, 2007; 67(20): 9887 - 9893. [Abstract] [Full Text] [PDF]
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C. A. Ritter, M. Perez-Torres, C. Rinehart, M. Guix, T. Dugger, J. A. Engelman, and C. L. Arteaga Human Breast Cancer Cells Selected for Resistance to Trastuzumab In vivo Overexpress Epidermal Growth Factor Receptor and ErbB Ligands and Remain Dependent on the ErbB Receptor Network Clin. Cancer Res., August 15, 2007; 13(16): 4909 - 4919. [Abstract] [Full Text] [PDF]
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 N. L. Spector, Y. Yarden, B. Smith, L. Lyass, P. Trusk, K. Pry, J. E. Hill, W. Xia, R. Seger, and S. S. Bacus Activation of AMP-activated protein kinase by human EGF receptor 2/EGF receptor tyrosine kinase inhibitor protects cardiac cells PNAS, June 19, 2007; 104(25): 10607 - 10612. [Abstract] [Full Text] [PDF]
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A. Magnifico, L. Albano, S. Campaner, M. Campiglio, S. Pilotti, S. Menard, and E. Tagliabue Protein Kinase C{alpha} Determines HER2 Fate in Breast Carcinoma Cells with HER2 Protein Overexpression without Gene Amplification Cancer Res., June 1, 2007; 67(11): 5308 - 5317. [Abstract] [Full Text] [PDF]
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C. Larbouret, B. Robert, I. Navarro-Teulon, S. Thezenas, M.-Z. Ladjemi, S. Morisseau, E. Campigna, F. Bibeau, J.-P. Mach, A. Pelegrin, et al. In vivo Therapeutic Synergism of Anti-Epidermal Growth Factor Receptor and Anti-HER2 Monoclonal Antibodies against Pancreatic Carcinomas Clin. Cancer Res., June 1, 2007; 13(11): 3356 - 3362. [Abstract] [Full Text] [PDF]
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J. S. Ross, W. F. Symmans, L. Pusztai, and G. N. Hortobagyi Standardizing Slide-Based Assays in Breast Cancer: Hormone Receptors, HER2, and Sentinel Lymph Nodes Clin. Cancer Res., May 15, 2007; 13(10): 2831 - 2835. [Abstract] [Full Text] [PDF]
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D. Palmieri, J. L. Bronder, J. M. Herring, T. Yoneda, R. J. Weil, A. M. Stark, R. Kurek, E. Vega-Valle, L. Feigenbaum, D. Halverson, et al. Her-2 Overexpression Increases the Metastatic Outgrowth of Breast Cancer Cells in the Brain Cancer Res., May 1, 2007; 67(9): 4190 - 4198. [Abstract] [Full Text] [PDF]
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D. Tripathy Capecitabine in Combination with Novel Targeted Agents in the Management of Metastatic Breast Cancer: Underlying Rationale and Results of Clinical Trials Oncologist, April 1, 2007; 12(4): 375 - 389. [Abstract] [Full Text] [PDF]
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J. T. Jorgensen, K. V. Nielsen, and B. Ejlertsen Pharmacodiagnostics and Targeted Therapies--A Rational Approach for Individualizing Medical Anticancer Therapy in Breast Cancer Oncologist, April 1, 2007; 12(4): 397 - 405. [Abstract] [Full Text] [PDF]
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V. Tolmachev, A. Orlova, R. Pehrson, J. Galli, B. Baastrup, K. Andersson, M. Sandstrom, D. Rosik, J. Carlsson, H. Lundqvist, et al. Radionuclide Therapy of HER2-Positive Microxenografts Using a 177Lu-Labeled HER2-Specific Affibody Molecule Cancer Res., March 15, 2007; 67(6): 2773 - 2782. [Abstract] [Full Text] [PDF]
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J. S. Fridman, E. Caulder, M. Hansbury, X. Liu, G. Yang, Q. Wang, Y. Lo, B.-B. Zhou, M. Pan, S. M. Thomas, et al. Selective Inhibition of ADAM Metalloproteases as a Novel Approach for Modulating ErbB Pathways in Cancer Clin. Cancer Res., March 15, 2007; 13(6): 1892 - 1902. [Abstract] [Full Text] [PDF]
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B. Lutterbach, Q. Zeng, L. J. Davis, H. Hatch, G. Hang, N. E. Kohl, J. B. Gibbs, and B.-S. Pan Lung Cancer Cell Lines Harboring MET Gene Amplification Are Dependent on Met for Growth and Survival Cancer Res., March 1, 2007; 67(5): 2081 - 2088. [Abstract] [Full Text] [PDF]
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W. Xia, I. Husain, L. Liu, S. Bacus, S. Saini, J. Spohn, K. Pry, R. Westlund, S. H. Stein, and N. L. Spector Lapatinib Antitumor Activity Is Not Dependent upon Phosphatase and Tensin Homologue Deleted on Chromosome 10 in ErbB2-Overexpressing Breast Cancers Cancer Res., February 1, 2007; 67(3): 1170 - 1175. [Abstract] [Full Text] [PDF]
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R. Nahta, L. X.H. Yuan, Y. Du, and F. J. Esteva Lapatinib induces apoptosis in trastuzumab-resistant breast cancer cells: effects on insulin-like growth factor I signaling Mol. Cancer Ther., February 1, 2007; 6(2): 667 - 674. [Abstract] [Full Text] [PDF]
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N. G. Dolloff, M. R. Russell, N. Loizos, and A. Fatatis Human Bone Marrow Activates the Akt Pathway in Metastatic Prostate Cells through Transactivation of the {alpha}-Platelet-Derived Growth Factor Receptor Cancer Res., January 15, 2007; 67(2): 555 - 562. [Abstract] [Full Text] [PDF]
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 C. E. Geyer, J. Forster, D. Lindquist, S. Chan, C. G. Romieu, T. Pienkowski, A. Jagiello-Gruszfeld, J. Crown, A. Chan, B. Kaufman, et al. Lapatinib plus Capecitabine for HER2-Positive Advanced Breast Cancer N. Engl. J. Med., December 28, 2006; 355(26): 2733 - 2743. [Abstract] [Full Text] [PDF]
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F. Meric-Bernstam and M.-C. Hung Advances in targeting human epidermal growth factor receptor-2 signaling for cancer therapy. Clin. Cancer Res., November 1, 2006; 12(21): 6326 - 6330. [Abstract] [Full Text] [PDF]
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B. Moy and P. E. Goss Lapatinib: Current Status and Future Directions in Breast Cancer Oncologist, November 1, 2006; 11(10): 1047 - 1057. [Abstract] [Full Text] [PDF]
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W. Xia, S. Bacus, P. Hegde, I. Husain, J. Strum, L. Liu, G. Paulazzo, L. Lyass, P. Trusk, J. Hill, et al. A model of acquired autoresistance to a potent ErbB2 tyrosine kinase inhibitor and a therapeutic strategy to prevent its onset in breast cancer PNAS, May 16, 2006; 103(20): 7795 - 7800. [Abstract] [Full Text] [PDF]
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