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Joaquin Arribas - One of the best experts on this subject based on the ideXlab platform.
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lapatinib a her2 Tyrosine Kinase Inhibitor induces stabilization and accumulation of her2 and potentiates trastuzumab dependent cell cytotoxicity
Oncogene, 2009Co-Authors: Maurizio Scaltriti, Chandra Verma, M Guzman, Jose Jimenez, Joseplluis Parra, Kim Pedersen, Derek Smith, Stefania Landolfi, Ramon S Y Cajal, Joaquin ArribasAbstract:Lapatinib, a HER2 Tyrosine Kinase Inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity
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Lapatinib, a HER2 Tyrosine Kinase Inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity
Oncogene, 2009Co-Authors: Maurizio Scaltriti, Chandra Verma, M Guzman, Jose Jimenez, Kim Pedersen, Stefania Landolfi, J L Parra, D J Smith, S Ramon Y Cajal, Joaquin ArribasAbstract:Lapatinib is a human epidermal growth factor receptor 2 (HER2) Tyrosine Kinase Inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo- (HER2/HER2) and hetero- (HER2/EGFR and HER2/HER3) dimers. Lapatinib-induced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo , where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.
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combined epidermal growth factor receptor targeting with the Tyrosine Kinase Inhibitor gefitinib zd1839 and the monoclonal antibody cetuximab imc c225 superiority over single agent receptor targeting
Clinical Cancer Research, 2004Co-Authors: Pablo Matar, Joaquin Arribas, Federico Rojo, Raul Cassia, Gema Morenobueno, Serena Di Cosimo, Jose Tabernero, Marta Guzman, S Rodriguez, Jose PalaciosAbstract:Purpose: The epidermal growth factor receptor (EGFR) is abnormally activated in cancer and two classes of anti-EGFR agents, monoclonal antibodies and low-molecular-weight Tyrosine Kinase Inhibitors, have shown antitumor activity in patients. Because these two classes of antireceptor agents target the EGFR at different sites, we decided to explore whether the combined administration of gefitinib, a Tyrosine Kinase Inhibitor, and cetuximab, a monoclonal antibody, had superior antitumor activity than either agent given alone. Experimental Design: We studied the effects of the combination of gefitinib and cetuximab in a panel of human cancer cell lines and in an EGFR-dependent human tumor xenograft model (A431). The effects of these two agents on EGFR signaling, proliferation, apoptosis, and vascularization were evaluated. In addition, we analyzed, with cDNA arrays, changes in gene expression profiles induced by both agents. Results: The combined treatment with gefitinib and cetuximab resulted in a synergistic effect on cell proliferation and in superior inhibition of EGFR-dependent signaling and induction of apoptosis. In a series of in vivo experiments, single-agent gefitinib or cetuximab resulted in transient complete tumor remission only at the highest doses. In contrast, suboptimal doses of gefitinib and cetuximab given together resulted in a complete and permanent regression of large tumors. In the combination-treated tumors, there was a superior inhibition of EGFR, mitogen-activated protein Kinase, and Akt phosphorylation, as well as greater inhibition of cell proliferation and vascularization and enhanced apoptosis. Using cDNA arrays, we found 59 genes that were coregulated and 45 genes differentially regulated, including genes related to cell proliferation and differentiation, transcription, DNA synthesis and repair, angiogenesis, signaling molecules, cytoskeleton organization, and tumor invasion and metastasis. Conclusions: Our findings suggest both shared and complementary mechanisms of action with gefitinib and cetuximab and support combined EGFR targeting as a clinically exploitable strategy.
James D Griffin - One of the best experts on this subject based on the ideXlab platform.
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inhibition of mutant flt3 receptors in leukemia cells by the small molecule Tyrosine Kinase Inhibitor pkc412
Cancer Cell, 2002Co-Authors: Ellen Weisberg, Christina L Boulton, Louise M Kelly, Paul W Manley, Doriano Fabbro, Thomas Meyer, Gary D Gilliland, James D GriffinAbstract:Abstract Constitutively activating FLT3 receptor mutations have been found in 35% of patients with acute myeloblastic leukemia (AML). Here we report the identification of a small molecule FLT3 Tyrosine Kinase Inhibitor PKC412, which selectively induced G1 arrest and apoptosis of Ba/F3 cell lines expressing mutant FLT3 (IC 50
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growth inhibition and modulation of Kinase pathways of small cell lung cancer cell lines by the novel Tyrosine Kinase Inhibitor sti 571
Oncogene, 2000Co-Authors: Wenlan Wang, James D Griffin, Martin Sattler, Mary Ellen Healy, Shalini Verma, Gautam Maulik, Charles D Stiles, Bruce E Johnson, Ravi SalgiaAbstract: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.
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mechanism of resistance to the abl Tyrosine Kinase Inhibitor sti571 in bcr abl transformed hematopoietic cell lines
Blood, 2000Co-Authors: Ellen Weisberg, James D GriffinAbstract:The Tyrosine Kinase activity of the Bcr/Abl oncogene is required for transformation of hematopoietic cells. The Tyrosine Kinase Inhibitor STI571 (formerly called CGP57148B, Novartis Pharmaceuticals) inhibits BCR/ABL, TEL/ABL, and v-ABL Kinase activity and inhibits growth and viability of cells transformed by any of these ABL oncogenes. Here we report the generation of 2 BCR/ABL–positive cell lines that have developed partial resistance to STI571. BCR/ABL–transformed Ba/F3 hematopoietic cells and Philadelphia-positive human K562 cells were cultured in gradually increasing concentrations of STI571 over a period of several months to generate resistant lines. Resistant Ba/F3.p210 cells were found to have an increase in Bcr/Abl messenger RNA, amplification of the Bcr/Abl transgene, and a greater than tenfold increase in the level of BCR/ABL protein. In contrast to Ba/F3.p210 cells, drug-resistant K562 cells did not undergo detectable amplification of the BCR/ABL gene, although they displayed a 2-fold to 3-fold increase in p210BCR/ABL protein. The addition of STI571 to both resistant Ba/F3.p210 and K562 cells resulted in a rapid reduction of Tyrosine phosphorylation of cellular proteins, similar to that observed for nonresistant cells. However, the inhibition of Kinase activity was transient and partial and was not accompanied by apoptosis. The results suggest that resistance to STI571 may be multifactorial. Increased expression of the target protein BCR/ABL was observed in both lines, and resulted from oncogene amplification in one line. However, altered drug metabolism, transport, or other related mechanisms may also contribute to drug resistance.
Steven D Averbuch - One of the best experts on this subject based on the ideXlab platform.
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selective oral epidermal growth factor receptor Tyrosine Kinase Inhibitor zd1839 is generally well tolerated and has activity in non small cell lung cancer and other solid tumors results of a phase i trial
Journal of Clinical Oncology, 2002Co-Authors: Roy S Herbst, A M Maddox, Mace L Rothenberg, Eric J Small, Eric H Rubin, Jose Baselga, Federico Rojo, Waun Ki Hong, Helen Swaisland, Steven D AverbuchAbstract:PURPOSE: To investigate safety, tolerability, dose-related pharmacologic properties, and pharmacodynamics of ZD1839 (gefinitib, Iressa; AstraZeneca Pharmacueticals, Wilmington, DE), an epidermal growth factor receptor (EGFR) Tyrosine Kinase Inhibitor, in patients with solid tumor types known to express or highly express EGFR. METHODS: This was an open-label, phase I, dose escalation safety/tolerability trial of oral ZD1839 (150 to 1,000 mg/d), administered once daily for 28-continuous-day cycles until disease progression or undue toxicity. RESULTS: Of 71 (69 assessable for safety; 58 for efficacy) patients at seven dose levels, most had non–small-cell lung (n = 39) or head and neck (n = 18) cancer, and 68 of 71 patients received prior cancer therapy (two or more regimens in 54 patients [78%]). Diarrhea and rash, the primary dose-limiting toxicities (DLTs), occurred at 800 mg. Frequent treatment-related grade 1/2 adverse events were diarrhea (55%), asthenia (44%), and acne-like follicular rash (46%). At do...
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zd1839 a selective oral epidermal growth factor receptor Tyrosine Kinase Inhibitor is well tolerated and active in patients with solid malignant tumors results of a phase i trial
Journal of Clinical Oncology, 2002Co-Authors: Malcolm R Ranson, Steven D Averbuch, Lisa A Hammond, David Ferry, Mark G Kris, Andrew Tullo, Philip I Murray, Vince Miller, Judith Ochs, Charles MorrisAbstract:PURPOSE: To investigate the tolerability, pharmacokinetics, and antitumor activity of the oral, selective epidermal growth factor receptor-Tyrosine Kinase Inhibitor ZD1839 in patients with solid malignant tumors. PATIENTS AND METHODS: This was an open, phase I, escalating multiple-dose tolerability and pharmacokinetic trial. ZD1839 was administered once daily for 14 consecutive days followed by 14 days off treatment. Dose escalation started at 50 mg/d and continued to 925 mg or until consistent dose-limiting toxicity (DLT) was observed. RESULTS: Sixty-four patients were entered at eight dose levels. The most frequent dose-related grade 1 and 2 adverse events were an acne-like (or folliculitis) rash, nausea, and diarrhea. Three of nine patients treated at 700 mg/d developed DLT (reversible grade 3 diarrhea); grade 3 and 4 events were uncommon. Exposure to ZD1839 was dose proportional, and the mean terminal half-life was 48 hours (range, 37 to 65). Four of 16 patients with non–small-cell lung cancer (NSCLC)...
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the Tyrosine Kinase Inhibitor zd1839 iressa inhibits her2 driven signaling and suppresses the growth of her2 overexpressing tumor cells
Cancer Research, 2001Co-Authors: Mark M Moasser, Andrea D Basso, Steven D Averbuch, Neal RosenAbstract:The epidermal growth factor receptor (EGFR) is commonly overexpressed in many human tumors and provides a new target for anticancer drug development. ZD1839 (“Iressa”), a quinazoline Tyrosine Kinase Inhibitor selective for the EGFR, has shown good activity in preclinical studies and in the early phase of clinical trials. However, because it remains unclear which tumor types are the best targets for treatment with this agent, the molecular characteristics that correlate with tumor sensitivity to ZD1839 have been studied. In a panel of human breast cancer and other epithelial tumor cell lines, HER2-overexpressing tumors were particularly sensitive to ZD1839. Growth inhibition of these tumor cell lines was associated with the dephosphorylation of EGFR, HER2, and HER3, accompanied by the loss of association of HER3 with phosphatidylinositol 3-Kinase, and down-regulation of Akt activity. These studies suggest that HER2-overexpressing tumors are particularly susceptible to the inhibition of HER family Tyrosine Kinase signaling and suggest novel strategies to treat these particularly aggressive tumors.
Oliver G Ottmann - One of the best experts on this subject based on the ideXlab platform.
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clinical pharmacokinetics of the bcr abl Tyrosine Kinase Inhibitor nilotinib
Clinical Pharmacology & Therapeutics, 2010Co-Authors: Chiaki Tanaka, Hagop M Kantarjian, Francis J. Giles, Venkat Sethuraman, Thomas M Smith, X Wang, K Grouss, Oliver G Ottmann, L Galitz, Horst SchranAbstract:This article describes studies that investigated the pharmacokinetics of nilotinib, a highly specific, oral, second-generation BCR–ABL Tyrosine Kinase Inhibitor. After a once- or twice-daily regimen at doses ranging from 50 to 1,200 mg/day in 119 patients with chronic myeloid leukemia (CML), the area under the serum concentration–time curve (AUC) and peak serum concentration (Cmax) of nilotinib were found to be nearly dose proportional up to a dose of 400 mg once daily. Solubility-limited absorption at higher doses was observed, but this was partially overcome by dividing the daily dose into two. For instance, the administration of 400 mg nilotinib twice daily resulted in a 35% increase in AUC as compared to a once-daily dose of 800 mg. Exploratory pharmacodynamic assessment showed a general trend of greater reduction in white blood cell (WBC) levels with increase in nilotinib concentrations. This finding was consistent with the observation of an 82% reduction in WBC levels in patients after a regimen of 400 mg nilotinib twice daily for 15 days. The type and quantity of food intake variably affected nilotinib absorption. When administered after a high-fat meal, the AUC of nilotinib increased by 50% in CML patients (n = 10) and by 82% in healthy volunteers (n = 44). Clinical Pharmacology & Therapeutics (2010) 87 2, 197–203. doi:10.1038/clpt.2009.208
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nilotinib formerly amn107 a highly selective bcr abl Tyrosine Kinase Inhibitor is active in patients with imatinib resistant or intolerant accelerated phase chronic myelogenous leukemia
Blood, 2008Co-Authors: Philipp Le Coutre, Jorge E Cortes, Francis J. Giles, Oliver G Ottmann, Norbert Gattermann, Jane F Apperley, Richard A Larson, Elisabetta Abruzzese, Stephen G Obrien, Kazimierz KuliczkowskiAbstract:Patients with imatinib-resistant or -intolerant accelerated-phase chronic myelogenous leukemia (CML-AP) have very limited therapeutic options. Nilotinib is a highly selective BCR-ABL Tyrosine Kinase Inhibitor. This phase 2 trial was designed to characterize the efficacy and safety of nilotinib (400 mg twice daily) in this patient population with hematologic response (HR) as primary efficacy endpoint. A total of 119 patients were enrolled and had a median duration of treatment of 202 days (range, 2–611 days). An HR was observed in 56 patients (47%; 95% confidence interval [CI], 38%-56%). Major cytogenetic response (MCyR) was observed in 35 patients (29%; 95% CI, 21%-39%). The median duration of HR has not been reached. Overall survival rate among the 119 patients after 12 months of follow-up was 79% (95% CI, 70%-87%). Nonhematologic adverse events were mostly mild to moderate. Severe peripheral edema and pleural effusions were not observed. The most common grade 3 or higher hematologic adverse events were thrombocytopenia (35%) and neutropenia (21%). Grade 3 or higher bilirubin and lipase elevations occurred in 9% and 18% of patients, respectively, resulting in treatment discontinuation in one patient. In conclusion, nilotinib is an effective and well-tolerated treatment in imatinib-resistant and -intolerant CML-AP. This trial is registered at [www.clinicaltrials.gov][1] as [NCT00384228][2]. [1]: http://www.clinicaltrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00384228&atom=%2Fbloodjournal%2F111%2F4%2F1834.atom
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ph acute lymphoblastic leukemia resistant to the Tyrosine Kinase Inhibitor sti571 has a unique bcr abl gene mutation
Blood, 2002Co-Authors: Wolfk Hofmann, Oliver G Ottmann, Letetia C Jones, Nathan A Lemp, Harald Gschaidmeier, Dieter Hoelzer, Phillip H KoefflerAbstract:The Tyrosine Kinase Inhibitor STI571 is a promising agent for the treatment of advanced Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL), but resistance develops rapidly in most patients after an initial response. To identify mechanisms of resistance to STI571, 30 complementary DNAs (including 9 matched samples) obtained from the bone marrow of individuals with Ph+ ALL were analyzed by direct sequencing of a 714–base pair region of ABL encoding for the adenosine triphosphate (ATP)–binding site and the Kinase activation loop. A single point mutation was found at nucleotide 1127 (GI6382056) resulting in Glu255Lys. This mutation occurred in 6 of 9 patients (67%) following their treatment with STI571 but not in the samples from patients before beginning treatment with STI571. Glu255Lys is within the motif important for forming the pocket of the ATP-binding site in ABL and it is highly conserved across species. In conclusion, Ph+ ALL samples resistant to STI571 have a unique mutation Glu255Lys of BCR-ABL.
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relation between resistance of philadelphia chromosome positive acute lymphoblastic leukaemia to the Tyrosine Kinase Inhibitor sti571 and gene expression profiles a gene expression study
The Lancet, 2002Co-Authors: Wolfk Hofmann, Harald Gschaidmeier, Dieter Hoelzer, Phillip H Koeffler, David Elashoff, Oliver G OttmannAbstract:Summary Background The ABL Tyrosine Kinase Inhibitor STI571 is a promising agent for treatment of advanced Philadelphia-chromosome-positive (Ph+) acute lymphoblastic leukaemia. However, resistance to this drug develops within a few months in most patients. We aimed to predict resistance to STI571. Methods Total RNA was extracted from 25 bone-marrow samples from 19 patients with Ph+ acute lymphoblastic leukaemia who were enrolled into a phase II study. 17 samples were obtained before STI571 treatment was started: ten from individuals who were classified as good responders to STI571 (sensitive), and seven from individuals who did not to respond to STI571 (primary resistance). Eight samples were obtained from patients during treatment with STI571. We analysed six matched samples, which were obtained before and during treatment with STI571. Oligonucleotide microarray analysis of samples was done with high-density microarrays. Findings We identified 95 genes whose expression could be used to predict sensitivity of leukaemic cells to STI571. On this basis, all the STI571-sensitive samples could clearly be distinguished from the resistant cases. 56 highly differentially expressed genes were identified in leukaemic cells that were secondarily resistant to STI571. Resistant leukaemic cells expressed high levels of Bruton's Tyrosine Kinase and two ATP synthetases ( ATP5A1 and ATP5C1 ), and showed significantly reduced expression of the proapoptotic gene BAK1 and the cell-cycle control gene p15 INK4b . Interpretation We have shown the clinical relevance of gene expression data for the pretreatment assessment of acute lymphoblastic leukaemia. Our results have implications for future clinical studies of Tyrosine Kinase Inhibitors.
Maurizio Scaltriti - One of the best experts on this subject based on the ideXlab platform.
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lapatinib a her2 Tyrosine Kinase Inhibitor induces stabilization and accumulation of her2 and potentiates trastuzumab dependent cell cytotoxicity
Oncogene, 2009Co-Authors: Maurizio Scaltriti, Chandra Verma, M Guzman, Jose Jimenez, Joseplluis Parra, Kim Pedersen, Derek Smith, Stefania Landolfi, Ramon S Y Cajal, Joaquin ArribasAbstract:Lapatinib, a HER2 Tyrosine Kinase Inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity
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Lapatinib, a HER2 Tyrosine Kinase Inhibitor, induces stabilization and accumulation of HER2 and potentiates trastuzumab-dependent cell cytotoxicity
Oncogene, 2009Co-Authors: Maurizio Scaltriti, Chandra Verma, M Guzman, Jose Jimenez, Kim Pedersen, Stefania Landolfi, J L Parra, D J Smith, S Ramon Y Cajal, Joaquin ArribasAbstract:Lapatinib is a human epidermal growth factor receptor 2 (HER2) Tyrosine Kinase Inhibitor (TKI) that has clinical activity in HER2-amplified breast cancer. In vitro studies have shown that lapatinib enhances the effects of the monoclonal antibody trastuzumab suggesting partially non-overlapping mechanisms of action. To dissect these mechanisms, we have studied the effects of lapatinib and trastuzumab on receptor expression and receptor signaling and have identified a new potential mechanism for the enhanced antitumor activity of the combination. Lapatinib, given alone or in combination with trastuzumab to HER2-overexpressing breast cancer cells SKBR3 and MCF7-HER2, inhibited HER2 phosphorylation, prevented receptor ubiquitination and resulted in a marked accumulation of inactive receptors at the cell surface. By contrast, trastuzumab alone caused enhanced HER2 phosphorylation, ubiquitination and degradation of the receptor. By immunoprecipitation and computational protein modeling techniques we have shown that the lapatinib-induced HER2 accumulation at the cell surface also results in the stabilization of inactive HER2 homo- (HER2/HER2) and hetero- (HER2/EGFR and HER2/HER3) dimers. Lapatinib-induced accumulation of HER2 and trastuzumab-mediated downregulation of HER2 was also observed in vivo , where the combination of the two agents triggered complete tumor remissions in all cases after 10 days of treatment. Accumulation of HER2 at the cell surface by lapatinib enhanced immune-mediated trastuzumab-dependent cytotoxicity. We propose that this is a novel mechanism of action of the combination that may be clinically relevant and exploitable in the therapy of patients with HER2-positive tumors.
