242 research outputs found
The Brown–Halmos theorem for discrete Wiener–Hopf operators
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© The Author(s) 2024.We prove an analogue of the Brown–Halmos theorem for discrete Wiener–Hopf operators acting on separable rearrangement-invariant Banach sequence spaces.publishersversionpublishe
Hypersensitivity in ALK-positive lung cancers exposed to ALK inhibitors: a case of successful switch to an alternative ALK inhibitor and systematic review of the literature
No full textLei Deng,1 Janaki Sharma,2 Elizabeth Ravera,2 Balazs Halmos,2 Haiying Cheng2 1Department of Medicine, Jacobi Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA; 2Department of Oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, NY, USA Abstract: Alectinib can cause rare, but severe hypersensitivity. The cross-reactivity between different ALK inhibitors is unknown and desensitization is the only reported management. We hereby report the first case of severe delayed hypersensitivity developed in a lung cancer patient treated by alectinib, who was successfully managed by switching to brigatinib, another ALK inhibitor. The patient achieved excellent anti-tumor response to brigatinib. Our case provides an alternative and safe strategy in patients with alectinib-related hypersensitivity. Keywords: alectinib, brigatini
EGFR T790M: revealing the secrets of a gatekeeper
No full textBrian Ko, Daniel Paucar, Balazs Halmos Department of Oncology, Montefiore Medical Center, Albert Einstein College of Medicine, New York, NY, USA Abstract: Non-small-cell lung cancers that harbor activating mutations in the EGFR gene represent an important molecularly defined subset of lung cancer. Despite dramatic initial responses with first- and second-generation EGFR-directed tyrosine-kinase inhibitors (TKIs) against these cancers, the development of a dominant and frequent resistance mechanism through a threonine–methionine amino acid substitution at position 790 (T790M) of EGFR has limited the long-term efficacy of these targeted therapies. This “gatekeeper” EGFR T790M alteration remains the only validated and relevant second-site resistance mutation for EGFR, allowing for focused research to understand and overcome EGFR T790M-mediated resistance. The current review focuses on EGFR T790M by discussing mechanisms of resistance mediated by EGFR T790M, reviewing development of novel third-generation EGFR TKIs targeting EGFR T790M, and highlighting current research on overcoming resistance to third-generation EGFR T790M TKIs. Keywords: lung cancer, epidermal growth factor receptor, T790M, targeted therapy, resistanc
Abstract 1217: Blockade of Aurora kinase A synergizes with platinum and radiation in non-small cell lung cancer cells
No full textAbstract
Background: Most patients with advanced lung cancer will receive platinum-based therapy during their treatment course despite limited clinical benefits. Thus, strategies to improve platinum-based therapy continue to be needed. Through a functional genetic screen, we have identified Aurora kinase A as a potentially actionable candidate that can modulate the activity of platinum compounds. Aurora A is a serine/threonine kinase and a key regulator of the mitotic process. Through its mitotic and non-mitotic roles, the aberrant activation of Aurora A can lead to oncogenic transformation and has emerged as a promising therapeutic target in cancer.
METHODS: High-throughput RNAi screen was used to identify potential candidates for cisplatin resistance. Cell proliferation/viability was determined by MTS assays and colony formation assays. Immunohistochemistry was performed to determine the overexpression of Aurora A in specimens from lung cancer patients. Western blot was used to explore the cell signaling mechanisms in cisplatin, radiation, and/or MLN8237 (alisertib) treated NSCLC cell lines. β-Galactosidase staining was performed to determine the senescence following cisplatin and/or MLN8237 treatment in NSCLC cell lines.
RESULTS: Aurora Kinase A is widely expressed in lung cancer specimens. The expression of Aurora A is upregulated following treatment with Cisplatin in NSCLC cells, such as PC9, A549, H1703, and H460. Inhibition of Aurora A activity with either siRNA-mediated knockdown or pharmacological blockade (MLN8237) significantly improved sensitivities to cisplatin and ionizing radiation, both of which cause DNA damage and cell death. On the other hand, inhibition of Aurora A activity by itself was associated with reduced cell proliferation and survival of NSCLC cell lines. Moreover, co-administration with Cisplatin and AURKA siRNA resulted in sustained DNA double strand breaks and more pronounced apoptosis. The combination of AURKA inhibitor (MLN8237) with Cisplatin similarly led to enhanced DNA damage. Similar effects were observed with radiation concomitant with inhibition of Aurora A. Furthermore, MLN8237 induced marked apoptosis in the p53 mutant cell line, PC9, whereas more senescence was noted in p53 wild type A549 cells.
CONCLUSIONS: Our study indicates a significant role for Aurora Kinase A as a common modulator of p53-dependent resistance in the context of DNA-damaging platinum and radiation therapy. Aurora A inhibition can potentially improve the efficacy of these common treatment modalities in lung cancer management.
Citation Format: Huijie Liu, Dongwei Zhang, Alain Borczuk, Vincent Chau, Roman Perez-Soler, Balazs Halmos, Haiying Cheng. Blockade of Aurora kinase A synergizes with platinum and radiation in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1217. doi:10.1158/1538-7445.AM2017-1217</jats:p
Abstract 518: Synergistic effects of dual inhibition of YAP1 and TAZ in non-small cell lung cancer cells
No full textAbstract
Background: The Hippo signaling pathway is associated with regulation of cell growth and apoptosis. Downstream effectors of this pathway, YAP and its paralog, TAZ, interact with TEA domain (TEAD) transcription factors leading to cell proliferation and anti-apoptosis. As a result, YAP and TAZ have emerged as attractive anti-cancer therapeutic targets. Several studies, including our previous report, have noted the individual effects of YAP or TAZ ablation; however, consequences of dual inhibition have not yet been investigated in lung cancer. We hypothesize that dual inhibition of YAP and TAZ will lead to more pronounced cytotoxicity than each knockdown alone as a result of diminished compensatory mechanism by the remaining family member.
Methods: NSCLC cell lines, such as PC9 and A549, were transfected with individual YAP1, TAZ siRNA or a combination of both siRNAs. Western blotting was performed to determine the levels of YAP1 and TAZ proteins following knockdown. Quantitative RT-PCR was also performed to confirm effective YAP1 and TAZ knockdown. In addition, gene and protein expression of downstream targets, such as CTGF and Cyr61, were assessed. Clonogenic assays were performed to determine cell survival.
Results: Successful siRNA-mediated YAP and TAZ ablation were confirmed with Western blot and qRT-PCR. The expression of the Hippo-YAP/TAZ downstream targets, CTGF, Cyr61 and AXL, were also reduced accordingly. Moreover, dual knockdown of YAP and TAZ led to a more pronounced inhibition of cell survival/proliferation than ablation of individual genes alone. In addition, dual inhibition of YAP/TAZ exhibited significantly diminished levels of the mesenchymal markers, vimentin and N-cadherin, and increased levels of the epithelial marker, E-cadherin. EMT has been recognized as an essential process during lung cancer tumor migration and metastasis.
Conclusion: Our findings show that dual inhibition of YAP1 and TAZ are synergistic in blocking NSCLC cell survival signaling. Thus, dual inhibition may serve as a better therapeutic strategy in targeting the Hippo pathway than sole YAP1 blockade in the management of NSCLC.
Citation Format: Elaine Shum, Huijie Liu, Liang Zhu, Roman Perez-Soler, Balazs Halmos, Haiying Cheng. Synergistic effects of dual inhibition of YAP1 and TAZ in non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 518. doi:10.1158/1538-7445.AM2017-518</jats:p
MET–GRB2 Signaling-Associated Complexes Correlate with Oncogenic MET Signaling and Sensitivity to MET Kinase Inhibitors
No full textAbstract
Purpose: Targeting MET in cancer is hampered by lack of diagnostics that accurately reflect high MET signaling and dependence. We hypothesized that assays reflecting MET signaling associated protein complexes could redefine tumors dependent on MET and could add additional precision beyond genomic assessments.
Experimental Design: We used biochemical approaches, cellular viability studies, and proximity ligation assays to assess MET dependence. We examined MET signaling complexes in lung cancer patient specimens (N = 406) and patient-derived xenograft (PDX) models of solid tumors (N = 308). We evaluated response to crizotinib in a MET-amplified cohort of PDX models of lung cancer (N = 6) and provide a case report of a lung cancer patient harboring a Δexon14 MET splice variant.
Results: We found the interaction of MET with the adaptor protein GRB2 is necessary for oncogenic survival signaling by MET. MET-GRB2 complexes were identified only within MET-amplified PDX models and patient specimens but exhibit substantial variability. Lack of MET-GRB2 complexes was associated with lack of response to MET TKI in cell lines and PDX models. Presence of MET-GRB2 complexes can further subtype tumors with Δexon14 MET splice variants. Presence of these complexes correlated with response to crizotinib in one patient with Δexon14 MET lacking MET gene amplification.
Conclusions: Proximity assays measuring MET-GRB2 signaling complexes provide novel insights into MET-mediated signaling and could complement current clinical genomics-based assay platforms. Clin Cancer Res; 23(22); 7084–96. ©2017 AACR.</jats:p
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