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  • American Association for Cancer Research (AACR)  (9)
  • 1
    Online Resource
    Online Resource
    B7-H3 Negatively Modulates CTL-Mediated Cancer Immunity
    American Association for Cancer Research (AACR) ; 2018
    In:  Clinical Cancer Research Vol. 24, No. 11 ( 2018-06-01), p. 2653-2664
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 24, No. 11 ( 2018-06-01), p. 2653-2664
    Abstract: Purpose: Anti-programmed-death-1 (PD-1) immunotherapy improves survival in non–small cell lung cancer (NSCLC), but some cases are refractory to treatment, thereby requiring alternative strategies. B7-H3, an immune-checkpoint molecule, is expressed in various malignancies. To our knowledge, this study is the first to evaluate B7-H3 expression in NSCLCs treated with anti-PD-1 therapy and the therapeutic potential of a combination of anti-PD-1 therapy and B7-H3 targeting. Experimental Design: B7-H3 expression was evaluated immunohistochemically in patients with NSCLC (n = 82), and its relationship with responsiveness to anti-PD-1 therapy and CD8+ tumor-infiltrating lymphocytes (TILs) was analyzed. The antitumor efficacy of dual anti-B7-H3 and anti-programmed death ligand-1 (PD-L1) antibody therapy was evaluated using a syngeneic murine cancer model. T-cell numbers and functions were analyzed by flow cytometry. Results: B7-H3 expression was evident in 74% of NSCLCs and was correlated critically with nonresponsiveness to anti-PD-1 immunotherapy. A small number of CD8+ TILs was observed as a subpopulation with PD-L1 tumor proportion score less than 50%, whereas CD8+ TILs were still abundant in tumors not expressing B7-H3. Anti-B7-H3 blockade showed antitumor efficacy accompanied with an increased number of CD8+ TILs and recovery of effector function. CD8+ T-cell depletion negated antitumor efficacy induced by B7-H3 blockade, indicating that improved antitumor immunity is mediated by CD8+ T cells. Compared with a single blocking antibody, dual blockade of B7-H3 and PD-L1 enhanced the antitumor reaction. Conclusions: B7-H3 expressed on tumor cells potentially circumvents CD8+-T-cell–mediated immune surveillance. Anti-B7-H3 immunotherapy combined with anti-PD-1/PD-L1 antibody therapy is a promising approach for B7-H3–expressing NSCLCs. Clin Cancer Res; 24(11); 2653–64. ©2018 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-17-2852
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2018
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 2
    Online Resource
    Online Resource
    Addition of S-1 to the Epidermal Growth Factor Receptor Inhibitor Gefitinib Overcomes Gefitinib Resistance in Non–small cell Lung Cancer Cell Lines with MET Amplification
    American Association for Cancer Research (AACR) ; 2009
    In:  Clinical Cancer Research Vol. 15, No. 3 ( 2009-02-01), p. 907-913
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 15, No. 3 ( 2009-02-01), p. 907-913
    Abstract: Purpose: Most non–small cell lung cancer (NSCLC) tumors with activating mutations in the epidermal growth factor receptor (EGFR) are initially responsive to EGFR tyrosine kinase inhibitors (EGFR-TKI) such as gefitinib and erlotinib, but they almost invariably develop resistance to these drugs. A secondary mutation in EGFR (T790M) and amplification of the MET proto-oncogene have been identified as mechanisms of such acquired resistance to EGFR-TKIs. We have now investigated whether addition of the oral fluoropyrimidine derivative S-1 to gefitinib might overcome gefitinib resistance in NSCLC cell lines. Experimental Design: The effects of gefitinib on EGFR signaling and on the expression both of thymidylate synthase and of the transcription factor E2F-1 in gefitinib-resistant NSCLC cells were examined by immunoblot analysis. The effects of S-1 (or 5-fluorouracil) and gefitinib on the growth of NSCLC cells were examined in vitro as well as in nude mice. Results: Gefitinib induced down-regulation of thymidylate synthase and E2F-1 in gefitinib-resistant NSCLC cells with MET amplification but not in those harboring the T790M mutation of EGFR. The combination of 5-fluorouracil and gefitinib synergistically inhibited the proliferation of cells with MET amplification, but not that of those with the T790M mutation of EGFR, in vitro. Similarly, the combination of S-1 and gefitinib synergistically inhibited the growth only of NSCLC xenografts with MET amplification. Conclusions: Our results suggest that the addition of S-1 to EGFR-TKIs is a promising strategy to overcome EGFR-TKI resistance in NSCLC with MET amplification.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-08-2251
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2009
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 3
    Online Resource
    Online Resource
    Abstract 4446: Activation of HER Family signaling as a mechanism of acquired resistance to ALK Inhibitors in EML4-ALK-positive Non-Small Cell Lung Cancer.
    American Association for Cancer Research (AACR) ; 2013
    In:  Cancer Research Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4446-4446
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 73, No. 8_Supplement ( 2013-04-15), p. 4446-4446
    Abstract: Purpose: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) such as crizotinib show marked efficacy in patients with non-small cell lung cancer positive for the echinoderm microtubule-associated protein-like 4 (EML4)-ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. Experimental Design: We established lines of EML4-ALK-positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK-positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristic. Results: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of the epidermal growth factor receptor (EGFR), HER2, and HER3 was up-regulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal-regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. Conclusions: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK. Citation Format: Junko Tanizaki, Isamu Okamoto, Takafumi Okabe, Kazuko Sakai, Kaoru Tanaka, Hidetoshi Hayashi, Hiroyasu Kaneda, Ken Takezawa, Kazuto Nishio, Kazuhiko Nakagawa. Activation of HER Family signaling as a mechanism of acquired resistance to ALK Inhibitors in EML4-ALK-positive Non-Small Cell Lung Cancer. [abstract] . In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4446. doi:10.1158/1538-7445.AM2013-4446
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2013-4446
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2013
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 4
    Online Resource
    Online Resource
    Abstract 1736: Src inhibitor dasatinib enhances anti-tumor activity of irreversible or T790M-selective epidermal growth factor receptor-tyrosine kinase inhibitors in non-small cell lung cancer cells with T790M gate-keeper mutation
    American Association for Cancer Research (AACR) ; 2011
    In:  Cancer Research Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1736-1736
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 71, No. 8_Supplement ( 2011-04-15), p. 1736-1736
    Abstract: Despite the therapeutic benefit of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in non-small cell lung cancer (NSCLC) patients with EGFR mutation, most if not all eventually develop resistance to these drugs. A secondary mutation of EGFR (T790M) accounts for 50% of all cases of acquired resistance to EGFR-TKIs. Although irreversible EGFR-TKIs are thought to be one of the strategies to overcome T790M, the efficacy of these drugs appears limited. To investigate how signal transduction is altered in NSCLC cells with T790M, we generated PC9GR cells with T790M by long term gefitinib exposure of PC9 cells with exon 19 deletion. Global phospho-proteomics approach revealed that Src family kinases were phosphorylated by erlotinib treatment in PC9GR cells, suggesting that Src family kinases compensate EGFR inhibition in NSCLC cells with T790M. Western blot assays demonstrated that BIBW2992, an irreversible EGFR-TKI currently in several clinical trials, also activated Src family kinases in PC9GR and H1975 NSCLC cells with T790M. The Src inhibitor dasatinib combined with BIBW2992 abolished this Src phosphorylation along with complete suppression of phospho Akt and Erk. In addition, significant PARP cleavage was observed in these cells suggesting apoptotic cell death. Consistent with the effects on cell signaling and apoptosis, dasatinib enhances anti-tumor activity of BIBW2992 in both GLO cell proliferation assay and caspase-3 apoptosis assay in PC9GR and H1975 cells. Additional experiments also demonstrated that dasatinib enhanced the effects of T790M selective EGFR-TKI WZ4002, which was recently reported to be another possible strategy to overcome T790M, in PC9GR and H1975 cells. Finally, the combination of BIBW2992 and dasatinib showed significant in vivo tumor suppression (including tumor regression) in PC9GR xenograft studies. These results suggest a role for Src in maintaining downstream signaling despite irreversible EGFR inhibitors and support further studies of irreversible EGFR combined with dasatinib in NSCLC patients who acquired resistance to EGFR-TKI by T790M. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1736. doi:10.1158/1538-7445.AM2011-1736
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2011-1736
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2011
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 5
    Online Resource
    Online Resource
    Differential Constitutive Activation of the Epidermal Growth Factor Receptor in Non–Small Cell Lung Cancer Cells Bearing EGFR Gene Mutation and Amplification
    American Association for Cancer Research (AACR) ; 2007
    In:  Cancer Research Vol. 67, No. 5 ( 2007-03-01), p. 2046-2053
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 67, No. 5 ( 2007-03-01), p. 2046-2053
    Abstract: The identification of somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) in patients with non–small cell lung cancer (NSCLC) and the association of such mutations with the clinical response to EGFR tyrosine kinase inhibitors (TKI), such as gefitinib and erlotinib, have had a substantial effect on the treatment of this disease. EGFR gene amplification has also been associated with an increased therapeutic response to EGFR-TKIs. The effects of these two types of EGFR alteration on EGFR function have remained unclear, however. We have now examined 16 NSCLC cell lines, including eight newly established lines from Japanese NSCLC patients, for the presence of EGFR mutations and amplification. Four of the six cell lines that harbor EGFR mutations were found to be positive for EGFR amplification, whereas none of the 10 cell lines negative for EGFR mutation manifested EGFR amplification, suggesting that these two types of EGFR alteration are closely associated. Endogenous EGFRs expressed in NSCLC cell lines positive for both EGFR mutation and amplification were found to be constitutively activated as a result of ligand-independent dimerization. Furthermore, the patterns of both EGFR amplification and EGFR autophosphorylation were shown to differ between cell lines harboring the two most common types of EGFR mutation (exon 19 deletion and L858R point mutation in exon 21). These results reveal distinct biochemical properties of endogenous mutant forms of EGFR expressed in NSCLC cell lines and may have implications for treatment of this condition. [Cancer Res 2007;67(5):2046–53]
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/0008-5472.CAN-06-3339
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2007
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 6
    Online Resource
    Online Resource
    Activation of HER Family Signaling as a Mechanism of Acquired Resistance to ALK Inhibitors in EML4-ALK–Positive Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2012
    In:  Clinical Cancer Research Vol. 18, No. 22 ( 2012-11-15), p. 6219-6226
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 18, No. 22 ( 2012-11-15), p. 6219-6226
    Abstract: Purpose: Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKI) such as crizotinib show marked efficacy in patients with non–small cell lung cancer positive for the echinoderm microtubule-associated protein–like 4 (EML4)–ALK fusion protein. However, acquired resistance to these agents has already been described in treated patients, and the mechanisms of such resistance remain largely unknown. Experimental Design: We established lines of EML4-ALK–positive H3122 lung cancer cells that are resistant to the ALK inhibitor TAE684 (H3122/TR cells) and investigated their resistance mechanism with the use of immunoblot analysis, ELISA, reverse transcription and real-time PCR analysis, and an annexin V binding assay. We isolated EML4-ALK–positive lung cancer cells (K-3) from a patient who developed resistance to crizotinib and investigated their characteristics. Results: The expression of EML4-ALK was reduced at the transcriptional level, whereas phosphorylation of epidermal growth factor receptor (EGFR), HER2, and HER3 was upregulated, in H3122/TR cells compared with those in H3122 cells. This activation of HER family proteins was accompanied by increased secretion of EGF. Treatment with an EGFR-TKI induced apoptosis in H3122/TR cells, but not in H3122 cells. The TAE684-induced inhibition of extracellular signal–regulated kinase (ERK) and STAT3 phosphorylation observed in parental cells was prevented by exposure of these cells to exogenous EGF, resulting in a reduced sensitivity of cell growth to TAE684. K-3 cells also manifested HER family activation accompanied by increased EGF secretion. Conclusions: EGF-mediated activation of HER family signaling is associated with ALK-TKI resistance in lung cancer positive for EML4-ALK. Clin Cancer Res; 18(22); 6219–26. ©2012 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-12-0392
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2012
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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  • 7
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    Online Resource
    Synergistic antitumor effect of S-1 and the epidermal growth factor receptor inhibitor gefitinib in non-small cell lung cancer cell lines: role of gefitinib-induced down-regulation of thymidylate synthase
    American Association for Cancer Research (AACR) ; 2008
    In:  Molecular Cancer Therapeutics Vol. 7, No. 3 ( 2008-03-01), p. 599-606
    Details
    In: Molecular Cancer Therapeutics, American Association for Cancer Research (AACR), Vol. 7, No. 3 ( 2008-03-01), p. 599-606
    Abstract: Somatic mutations in the epidermal growth factor receptor (EGFR) gene are associated with the therapeutic response to EGFR tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). The response rate to these drugs remains low, however, in NSCLC patients with wild-type EGFR alleles. Combination therapies with EGFR-TKIs and cytotoxic agents are considered a therapeutic option for patients with NSCLC expressing wild-type EGFR. We investigated the antiproliferative effect of the combination of the oral fluorouracil S-1 and the EGFR-TKI gefitinib in NSCLC cells of differing EGFR status. The combination of 5-fluorouracil and gefitinib showed a synergistic antiproliferative effect in vitro in all NSCLC cell lines tested. Combination chemotherapy with S-1 and gefitinib in vivo also had a synergistic antitumor effect on NSCLC xenografts regardless of the absence or presence of EGFR mutations. Gefitinib inhibited the expression of the transcription factor E2F-1, resulting in the down-regulation of thymidylate synthase at the mRNA and protein levels. These observations suggest that gefitinib-induced down-regulation of thymidylate synthase is responsible, at least in part, for the synergistic antitumor effect of combined treatment with S-1 and gefitinib and provide a basis for clinical evaluation of combination chemotherapy with S-1 and EGFR-TKIs in patients with solid tumors. [Mol Cancer Ther 2008;7(3):599–606]
    Type of Medium: Online Resource
    ISSN: 1535-7163 , 1538-8514
    URL: Article
    DOI: 10.1158/1535-7163.MCT-07-0567
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2008
    detail.hit.zdb_id: 2062135-8
    SSG: 12
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  • 8
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    Abstract 2136: Doublecortin-like Kinase 1 (DCLK1) correlates with the cell proliferation in malignant pleural mesothelioma
    American Association for Cancer Research (AACR) ; 2019
    In:  Cancer Research Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2136-2136
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 79, No. 13_Supplement ( 2019-07-01), p. 2136-2136
    Abstract: Background: Malignant pleural mesothelioma (MPM) is a refractory disease with poor prognosis despite multimodality therapy. Because standard therapy is unsatisfactory, it is expected to establish a novel strategy such as molecular-targeting therapy for MPM. Doublecortin-like kinase 1 (DCLK1), a microtubule-associated protein, is one of the tumor-specific stem cell marker and is revealed that the cell survival is reduced by inhibiting this protein in pancreatic and colorectal cancers. DCLK1 is known to have several isoforms named as isoform #1-#4, although the significance of them in MPM has not been clarified. We hypothesized that DCLK1 was a potential therapeutic target for MPM. & lt;Materials and Methods: Immunohistochemical staining was performed using surgically resected formalin-fixed paraffin-embedded tissue of MPM to evaluate the expression of DCLK1. Additionally, MPM cell lines were analyzed to characterize the protein and mRNA expression of DCLK1 by western blotting and RT-PCR. The expression of DCLK1 isoforms were selectively knocked down by small interfering RNA (siRNA) and cell viability was analyzed by colony formation and cell count assays. Results: Immunohistochemical staining demonstrated that the expression of DCLK1 in MPM specimens was positive in 24 out of 27 samples (89%). Western blotting and RT-PCR revealed that DCLK1 was expressed in seven out of nine MPM cell lines. The results of RT-PCR revealed that isoform #2 and isoform #4 of DCLK1 were expressed in H2052, isoform #4 was expressed in H28, and isoform #2 was expressed in YUMC44 cell lines. Expressions of DCLK1 isoforms were selectively suppressed by isoform-specific siRNAs. Colony formation and cell count assays revealed that siRNA-mediated knockdown of both isoforms #2 and #4 suppressed cell growth compared to knockdown by negative control siRNA and knockdown of only isoform #2 or #4. Conclusion: Our results demonstrate that simultaneous knockdown of both isoforms #2 and #4of DCLK1 results in the inhibition of cell growth and suggest its potential as a therapeutic target in MPM. Citation Format: Akihiro Miura, Hiromasa Yamamoto, Hiroyuki Tao, Ken Suzawa, Syunsaku Miyauchi, Kota Araki, Yuta Takahashi, Eisuke Kurihara, Yusuke Ogoshi, Kazuhiko Shien, Junichi Soh, Kazunori Okabe, Shuta Tomida, Masakiyo Sakaguchi, Shinichi Toyooka. Doublecortin-like Kinase 1 (DCLK1) correlates with the cell proliferation in malignant pleural mesothelioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2136.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2019-2136
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2019
    detail.hit.zdb_id: 2036785-5
    detail.hit.zdb_id: 1432-1
    detail.hit.zdb_id: 410466-3
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  • 9
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    Tyrosine Phosphoproteomics Identifies Both Codrivers and Cotargeting Strategies for T790M-Related EGFR-TKI Resistance in Non–Small Cell Lung Cancer
    American Association for Cancer Research (AACR) ; 2014
    In:  Clinical Cancer Research Vol. 20, No. 15 ( 2014-08-01), p. 4059-4074
    Details
    In: Clinical Cancer Research, American Association for Cancer Research (AACR), Vol. 20, No. 15 ( 2014-08-01), p. 4059-4074
    Abstract: Purpose: Irreversible EGFR-tyrosine kinase inhibitors (TKI) are thought to be one strategy to overcome EGFR-TKI resistance induced by T790M gatekeeper mutations in non–small cell lung cancer (NSCLC), yet they display limited clinical efficacy. We hypothesized that additional resistance mechanisms that cooperate with T790M could be identified by profiling tyrosine phosphorylation in NSCLC cells with acquired resistance to reversible EGFR-TKI and harboring T790M. Experimental Design: We profiled PC9 cells with TKI-sensitive EGFR mutation and paired EGFR-TKI–resistant PC9GR (gefitinib-resistant) cells with T790M using immunoaffinity purification of tyrosine-phosphorylated peptides and mass spectrometry–based identification/quantification. Profiles of erlotinib perturbations were examined. Results: We observed a large fraction of the tyrosine phosphoproteome was more abundant in PC9- and PC9GR-erlotinib–treated cells, including phosphopeptides corresponding to MET, IGF, and AXL signaling. Activation of these receptor tyrosine kinases by growth factors could protect PC9GR cells against the irreversible EGFR-TKI afatinib. We identified a Src family kinase (SFK) network as EGFR-independent and confirmed that neither erlotinib nor afatinib affected Src phosphorylation at the activation site. The SFK inhibitor dasatinib plus afatinib abolished Src phosphorylation and completely suppressed downstream phosphorylated Akt and Erk. Dasatinib further enhanced antitumor activity of afatinib or T790M-selective EGFR-TKI (WZ4006) in proliferation and apoptosis assays in multiple NSCLC cell lines with T790M-mediated resistance. This translated into tumor regression in PC9GR xenograft studies with combined afatinib and dasatinib. Conclusions: Our results identified both codrivers of resistance along with T790M and support further studies of irreversible or T790M-selective EGFR inhibitors combined with dasatinib in patients with NSCLC with acquired T790M. Clin Cancer Res; 20(15); 4059–74. ©2014 AACR.
    Type of Medium: Online Resource
    ISSN: 1078-0432 , 1557-3265
    URL: Article
    DOI: 10.1158/1078-0432.CCR-13-1559
    RVK:
    XA 36791
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2014
    detail.hit.zdb_id: 1225457-5
    detail.hit.zdb_id: 2036787-9
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