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Deric L Wheeler - One of the best experts on this subject based on the ideXlab platform.

  • Overcoming Resistance to Cetuximab with Honokiol, A Small-Molecule Polyphenol.
    Molecular Cancer Therapeutics, 2017
    Co-Authors: Hannah E. Pearson, Mari Iida, Rachel A. Orbuch, Nellie K. Mcdaniel, Kwangok P. Nickel, Randall J. Kimple, Jack L. Arbiser, Deric L Wheeler
    Abstract:

    Overexpression and activation of the EGFR have been linked to poor prognosis in several human cancers. Cetuximab is a mAb against EGFR that is used for the treatment in head and neck squamous cell carcinoma (HNSCC) and metastatic colorectal cancer. Unfortunately, most tumors have intrinsic or will acquire resistance to Cetuximab during the course of therapy. Honokiol is a natural compound found in the bark and leaves of the Chinese Magnolia tree and is established to have several anticancer properties without appreciable toxicity. In this study, we hypothesized that combining Cetuximab and honokiol treatments could overcome acquired resistance to Cetuximab. We previously developed a model of acquired resistance to Cetuximab in non–small cell lung cancer H226 cell line. Treatment of Cetuximab-resistant clones with honokiol and Cetuximab resulted in a robust antiproliferative response. Immunoblot analysis revealed the HER family and their signaling pathways were downregulated after combination treatment, most notably the proliferation (MAPK) and survival (AKT) pathways. In addition, we found a decrease in phosphorylation of DRP1 and reactive oxygen species after combination treatment in Cetuximab-resistant clones, which may signify a change in mitochondrial function. Furthermore, we utilized Cetuximab-resistant HNSCC patient-derived xenografts (PDX) to test the benefit of combinatorial treatment in vivo. There was significant growth delay in PDX tumors after combination treatment with a subsequent downregulation of active MAPK, AKT, and DRP1 signaling as seen in vitro. Collectively, these data suggest that honokiol is a promising natural compound in overcoming acquired resistance to Cetuximab. Mol Cancer Ther; 17(1); 204–14. ©2017 AACR.

  • Erlotinib is a viable treatment for tumors with acquired resistance to Cetuximab.
    Cancer Biology & Therapy, 2011
    Co-Authors: Toni M. Brand, Chunrong Li, Mari Iida, Emily F Dunn, Rebecca A. Myers, Kellie T. Kostopoulos, Chimera R. Peet, Deric L Wheeler
    Abstract:

    The epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase (RTK) and is recognized as a key mediator of tumorigenesis in many human tumors. Currently there are five EGFR inhibitors used in oncology, two monoclonal antibodies (panitumumab, and Cetuximab) and three tyrosine kinase inhibitors (erlotinib, gefitinib, and lapatinib). Both strategies of EGFR inhibition have demonstrated clinical successes, however many tumors remain non-responsive or acquire resistance during therapy. To explore potential molecular mechanisms of acquired resistance to Cetuximab we previously established a series of Cetuximab-resistant clones by chronically exposing the NCI-H226 NSCLC cell line to escalating doses of Cetuximab. Cetuximab-resistant clones exhibited a dramatic increase in steady-state expression of EGFR, HER2, and HER3 receptors as well as increased signaling through the MAPK and AKT pathways. RNAi studies demonstrated dependence of Cetuximab-resistant clones on the EGFR signal...

  • nuclear egfr contributes to acquired resistance to Cetuximab
    Oncogene, 2009
    Co-Authors: Chunrong Li, Mari Iida, Emily F Dunn, Amol J Ghia, Deric L Wheeler
    Abstract:

    Epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase involved in the etiology of several human cancers. Cetuximab is an EGFR-blocking antibody that has been approved for the treatment of patients with head and neck squamous cell carcinoma and metastatic colorectal cancer. Previous reports have shown that EGFR translocation to the nucleus is associated with cell proliferation. Here we investigated mechanisms of acquired resistance to Cetuximab using a model derived from the non-small cell lung cancer line H226. We demonstrated that Cetuximab-resistant cells overexpress HER family ligands including epidermal growth factor (EGF), amphiregulin, heparin-binding EGF and β-cellulin. Overexpression of these ligands is associated with the nuclear translocation of the EGFR and this process was mediated by the Src family kinases (SFK). Treatment of Cetuximab-resistant cells with the SFK inhibitor, dasatinib, resulted in loss of nuclear EGFR, increased membrane expression of the EGFR and resensitization to Cetuximab. In addition, expression of a nuclear localization sequence-tagged EGFR in Cetuximab-sensitive cells increased resistance to Cetuximab both in vitro and in mouse xenografts. Collectively, these data suggest that nuclear expression of EGFR may be an important molecular determinant of resistance to Cetuximab therapy and provides a rationale for investigating nuclear EGFR as a biomarker for Cetuximab response. Further, these data suggest a rationale for the design of clinical trials that examine the value of treating patients with Cetuximab-resistant tumors with inhibitors of SFKs in combination with Cetuximab.

  • mechanisms of acquired resistance to Cetuximab role of her erbb family members
    Oncogene, 2008
    Co-Authors: Deric L Wheeler, Shyhmin Huang, Tim J Kruser, Meghan M Nechrebecki, Eric A Armstrong, S Benavente, Vinai Gondi, Paul M Harari
    Abstract:

    The epidermal growth factor receptor (EGFR) is a central regulator of proliferation and progression in human cancers. Five EGFR inhibitors, two monoclonal antibodies and three TKIs, have recently gained FDA approval in oncology (Cetuximab, panitumumab, erlotinib, gefitinib and lapatinib). These strategies of EGFR inhibition demonstrate major tumor regressions in approximately 10–20% of advanced cancer patients. However, many tumors eventually manifest acquired resistance to treatment. In this study we established and characterized a model to study molecular mechanisms of acquired resistance to the EGFR monoclonal antibody Cetuximab. Using high-throughput screening we examined the activity of 42 receptor tyrosine kinases in resistant tumor cells following chronic exposure to Cetuximab. Cells developing acquired resistance to Cetuximab exhibited increased steady-state EGFR expression secondary to alterations in trafficking and degradation. In addition, Cetuximab-resistant cells manifested strong activation of HER2, HER3 and cMET. EGFR upregulation promoted increased dimerization with HER2 and HER3 leading to their transactivation. Blockade of EGFR and HER2 led to loss of HER3 and PI(3)K/Akt activity. These data suggest that acquired resistance to Cetuximab is accompanied by dysregulation of EGFR internalization/degradation and subsequent EGFR-dependent activation of HER3. Taken together these findings suggest a rationale for the clinical evaluation of combinatorial anti-HER targeting approaches in tumors manifesting acquired resistance to Cetuximab.

Wangjun Liao - One of the best experts on this subject based on the ideXlab platform.

  • inhibition of slc1a5 sensitizes colorectal cancer to Cetuximab
    International Journal of Cancer, 2018
    Co-Authors: Zhenzhen Wu, Hongxiang Huang, Jianjun Peng, Na Huang, Yulin Liao, Minyu Zhou, Lin Wang, Yi Liao, Yang Li, Wangjun Liao
    Abstract:

    : Cetuximab resistance is a key barrier in treating metastatic colorectal cancer (mCRC). Targeting of metabolic resources import could resensitize drug-resistant cancer cells to anticancer treatments. Here we showed that the expression of the glutamine transporter solute carrier 1 family member 5 (SLC1A5) in clinical CRC samples of patients resisted to Cetuximab was significantly higher than in those of patients responded to Cetuximab. Inhibition of SLC1A5 by shRNA-mediated gene silencing or pharmacological inhibitor significantly suppressed the growth of CRC. Moreover, inhibition of SLC1A5 significantly enhanced the inhibitory efficacy of Cetuximab on CRC proliferation both in vitro and in vivo. Mechanistically, SLC1A5 inhibition facilitated EGFR degradation through the ubiquitin-proteasome pathway, and decreased the expression of nuclear EGFR, both of which might have contribution to the improved response to Cetuximab. This study provides the metabolic molecule SLC1A5 as a potential therapeutic target to increase the efficacy of Cetuximab on CRC.

Yang Lu - One of the best experts on this subject based on the ideXlab platform.

  • asct2 slc1a5 is an egfr associated protein that can be co targeted by Cetuximab to sensitize cancer cells to ros induced apoptosis
    Cancer Letters, 2016
    Co-Authors: Xinqun Li, Haiquan Lu, Yang Lu
    Abstract:

    Therapeutic targeting of ASCT2, a glutamine transporter that plays a major role in glutamine uptake in cancer cells, is challenging because ASCT2 also has a biological role in normal tissues. In this study, we report our novel finding that ASCT2 is physically associated in a molecular complex with epidermal growth factor receptor (EGFR), which is often overexpressed in human head and neck squamous cell carcinoma (HNSCC). Furthermore, we found that ASCT2 can be co-targeted by Cetuximab, an EGFR antibody approved for treating metastatic HNSCC. We demonstrated that Cetuximab downregulated ASCT2 in an EGFR expression-dependent manner via Cetuximab-mediated EGFR endocytosis. Downregulation of ASCT2 by Cetuximab led to decreased intracellular uptake of glutamine and subsequently a decreased glutathione level. Cetuximab thereby sensitized HNSCC cells to reactive oxygen species (ROS)-induced apoptosis and, importantly, it is independent of effective inhibition of EGFR downstream signaling by Cetuximab. In contrast, knockdown of EGFR by siRNA or inhibition of EGFR kinase with gefitinib, an EGFR kinase inhibitor, failed to sensitize HNSCC cells to ROS-induced apoptosis. Our findings support a novel therapeutic strategy for EGFR-overexpressing and Cetuximab-resistant cancers by combining Cetuximab with an oxidative therapy.

  • Roles of autophagy in Cetuximab-mediated cancer therapy against EGFR.
    Autophagy, 2010
    Co-Authors: Xinqun Li, Yang Lu
    Abstract:

    Cetuximab is an epidermal growth factor receptor (EGFR)-blocking antibody that is approved to treat several types of solid cancers in patients. We recently showed that Cetuximab can induce autophagy in cancer cells by both inhibiting the class I phosphatidylinositol 3-kinase (PtdIns3K)/Akt/mammalian target of rapamycin (mTOR) pathway and activating the class III PtdIns3K (hVps34)/beclin 1 pathway. In the current study, we investigated the relationship between Cetuximab-induced autophagy and apoptosis and the biological roles of autophagy in Cetuximab-mediated cancer therapy. We found that Cetuximab induced autophagy in cancer cells that show strong or weak induction of apoptosis after Cetuximab treatment but not in those that show only cytostatic growth inhibition. Inhibition of Cetuximab-induced apoptosis by a caspase inhibitor prevented the induction of autophagy. Conversely, inhibition of Cetuximab-induced autophagy by silencing the expression of autophagy-related genes (Atg) or treating the cancer cells with lysosomal inhibitors enhanced the Cetuximab-induced apoptosis, suggesting that autophagy was a protective cellular response to Cetuximab treatment. On the other hand, cotreatment of cancer cells with Cetuximab and the mTOR inhibitor rapamycin resulted in an Atg-dependent and lysosomal inhibition-sensitive death of cancer cells that show only growth inhibition or weak apoptosis after Cetuximab treatment, indicating that cell death may be achieved by activating the autophagy pathway in these cells. Together, our findings may guide the development of novel clinical strategies for sensitizing cancer cells to EGFR-targeted therapy.

  • epidermal growth factor receptor egfr ubiquitination as a mechanism of acquired resistance escaping treatment by the anti egfr monoclonal antibody Cetuximab
    Cancer Research, 2007
    Co-Authors: Yang Lu, Xinqun Li, Gordon B. Mills, Ke Liang, Rodney B Luwor, Zahid H Siddik, John Mendelsohn
    Abstract:

    Cetuximab is an epidermal growth factor receptor (EGFR)–blocking antibody that has been approved for treatment of patients with metastatic colorectal cancer. In this study, we investigated biochemical changes in signaling pathways of a Cetuximab-resistant subline of DiFi colorectal cancer cells (DiFi5) that was developed by exposing the parental sensitive cells to subeffective doses of Cetuximab over an extended period of time. Compared with parental DiFi cells that express high levels of EGFR and in which Cetuximab induces apoptosis, the Cetuximab-resistant DiFi5 cells showed markedly lower protein levels of EGFR, an increased association of EGFR with Cbl, and an increased ubiquitination of EGFR. DiFi5 cells also had a markedly higher level of Src-Y416 phosphorylation both at baseline and on EGF stimulation. Although EGFR levels were low, DiFi5 cells responded to EGF stimulation with robust phosphorylation of EGFR on Y845 and strong phosphorylation of Akt and extracellular signal–regulated kinase, comparable to those of parental cells. Most importantly, inhibition of Src kinase activity with PP2 reversed the resistance of DiFi5 cells to Cetuximab-induced apoptosis without affecting the levels of EGFR in the cells. Our results indicate that colorectal cancer cells may develop acquired resistance to Cetuximab via altering EGFR levels through promotion of EGFR ubiquitination and degradation and using Src kinase-mediated cell signaling to bypass their dependency on EGFR for cell growth and survival. [Cancer Res 2007;67(17):8240–7]

Sabrina Arena - One of the best experts on this subject based on the ideXlab platform.

  • Abstract 2149: The anti-EGFR antibody mixture Sym004 overcomes acquired resistance to Cetuximab in colorectal cancer
    Cancer Research, 2016
    Co-Authors: Francisco J. Sánchez-martín, Joana Vidal, Israel Cañadas, Alba Dalmases, Guillem Argiles, Mariona Gelabert, Giulia Siravegna, Beatriz Bellosillo, Sabrina Arena, Klaus Koefoed
    Abstract:

    The anti-EGFR monoclonal antibodies (MoAbs) Cetuximab and panitumumab are used to treat ‘RAS’ wild type metastatic colorectal cancer (MCRC), providing significant clinical benefit in patients. However, all patients ultimately develop disease progression, driven by acquisition of mutations in downstream effectors and in the extracellular domain (ECD) of EGFR, in approximately 25% of the cases. Sym004 is a novel 1:1 mixture of two non-overlapping anti-EGFR MoAbs that has recently shown promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent Cetuximab resistance driven by EGFR ECD mutations. Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of Cetuximab, panitumumab and Sym004. Cell viability and molecular effects of the drugs were assayed in Cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to Cetuximab that harbored an EGFR mutation in the post-Cetuximab tumor sample. Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to Cetuximab harboring EGFR ECD mutations maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As a proof of principle, a patient with a tumor harboring an EGFR mutation (G465R) following Cetuximab therapy benefited from Sym004 therapy. These data suggest that Sym004 is an active drug in MCRC resistant to Cetuximab/panitumumab mediated by EGFR mutations. Overall, EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials. Citation Format: Francisco J. Sanchez-Martin, Alba Dalmases, Beatriz Bellosillo, Guillem Argiles, Mariona Gelabert, Israel Canadas, Joana Vidal, Giulia Siravegna, Sabrina Arena, Klaus Koefoed, Laura Visa, Oriol Arpi, Ivan D. Horak, Mar Iglesias, Christopher Stroh, Michael Kragh, Ana Rovira, Joan Albanell, Alberto Bardelli, Josep Tabernero, Clara Montagut. The anti-EGFR antibody mixture Sym004 overcomes acquired resistance to Cetuximab in colorectal cancer. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2149.

  • The first-in-class anti-EGFR antibody mixture Sym004 overcomes Cetuximab-resistance mediated by EGFR extracellular domain mutations in colorectal cancer
    Clinical Cancer Research, 2016
    Co-Authors: Francisco J. Sánchez-martín, Joana Vidal, Israel Cañadas, Alba Dalmases, Mariona Gelabert-baldrich, Guillem Argiles, Giulia Siravegna, Beatriz Bellosillo, Alejandro Gil-martínez, Sabrina Arena
    Abstract:

    Purpose: Approved anti-EGFR antibodies Cetuximab and panitumumab provide significant clinical benefit in patients with metastatic colorectal cancer (MCRC). However, patients ultimately develop disease progression, often driven by acquisition of mutations in the extracellular domain (ECD) of EGFR. Sym004 is a novel 1:1 mixture of two non-overlapping anti-EGFR monoclonal antibodies that recently showed promising clinical activity in a phase I trial in MCRC. Our aim was to determine the efficacy of Sym004 to circumvent Cetuximab resistance driven by EGFR ECD mutations. Experimental Design: Functional studies were performed to assess drug-receptor binding as well as ligand-dependent activation of individual EGFR mutants in the presence of Cetuximab, panitumumab and Sym004. Cell viability and molecular effects of the drugs were assayed in Cetuximab-resistant cell lines and in tumor xenograft models. Efficacy of Sym004 was evaluated in patients progressing to Cetuximab that harbored EGFR mutation in the post-Cetuximab tumor sample. Results: Contrary to Cetuximab and panitumumab, Sym004 effectively bound and abrogated ligand-induced phosphorylation of all individual EGFR mutants. Cells resistant to Cetuximab harboring mutations in EGFR maintained sensitivity to Sym004, which was consistent with an effective suppression of EGFR downstream signaling, translating into profound and sustained tumor regression in the xenograft model. As proof of principle, a patient with a tumor harboring an EGFR mutation (G465R) following Cetuximab therapy benefited from Sym004 therapy. Conclusions: Sym004 is an active drug in MCRC resistant to Cetuximab/panitumumab mediated by EGFR mutations. EGFR mutations are potential biomarkers of response to Sym004 to be evaluated in ongoing large clinical trials.

  • emergence of multiple egfr extracellular mutations during Cetuximab treatment in colorectal cancer
    Clinical Cancer Research, 2015
    Co-Authors: Sabrina Arena, Israel Cañadas, Giulia Siravegna, Beatriz Bellosillo, Alejandro Gil-martínez, Luca Lazzari, Noelia Ferruz, Mariangela Russo, Sandra Misale, Iria Gonzalez
    Abstract:

    Purpose: Patients with colorectal cancer who respond to the anti-EGFR antibody Cetuximab often develop resistance within several months of initiating therapy. To design new lines of treatment, the molecular landscape of resistant tumors must be ascertained. We investigated the role of mutations in the EGFR signaling axis on the acquisition of resistance to Cetuximab in patients and cellular models. Experimental Design: Tissue samples were obtained from 37 patients with colorectal cancer who became refractory to Cetuximab. Colorectal cancer cells sensitive to Cetuximab were treated until resistant derivatives emerged. Mutational profiling of biopsies and cell lines was performed. Structural modeling and functional analyses were performed to causally associate the alleles to resistance. Results: The genetic profile of tumor specimens obtained after Cetuximab treatment revealed the emergence of a complex pattern of mutations in EGFR , KRAS , NRAS , BRAF , and PIK3CA genes, including two novel EGFR ectodomain mutations (R451C and K467T). Mutational profiling of Cetuximab-resistant cells recapitulated the molecular landscape observed in clinical samples and revealed three additional EGFR alleles: S464L, G465R, and I491M. Structurally, these mutations are located in the Cetuximab-binding region, except for the R451C mutant. Functionally, EGFR ectodomain mutations prevent binding to Cetuximab but a subset is permissive for interaction with panitumumab. Conclusions: Colorectal tumors evade EGFR blockade by constitutive activation of downstream signaling effectors and through mutations affecting receptor–antibody binding. Both mechanisms of resistance may occur concomitantly. Our data have implications for designing additional lines of therapy for patients with colorectal cancer who relapse upon treatment with anti-EGFR antibodies. Clin Cancer Res; 21(9); 2157–66. ©2015 AACR .

David R Gandara - One of the best experts on this subject based on the ideXlab platform.

  • kras mutation analysis in Cetuximab treated advanced stage non small cell lung cancer nsclc swog experience with s0342 and s0536
    Journal of Clinical Oncology, 2009
    Co-Authors: P C Mack, Wilbur A. Franklin, W S Holland, Mary W Redman, P N Lara, L J Snyder, Fred R Hirsch, R S Herbst, David R Gandara
    Abstract:

    8022 Background: KRAS mutations occur in NSCLC with a frequency of 15–25% and have been associated with a poor response to EGFR tyrosine kinase inhibitors. In colorectal cancer, benefit from the EGFR-targeted monoclonal antibody Cetuximab is largely limited to patients (pts) whose tumors are KRAS wild-type (WT). However, in Cetuximab-treated NSCLC, a predictive role for KRAS mutations has not been established. We evaluated KRAS status in specimens from two Cetuximab-based front-line multicenter SWOG phase II trials in advanced NSCLC. Methods: DNA extracted from archival tumor and plasma specimens from S0342 (carboplatin-paclitaxel plus sequential vs. concurrent Cetuximab) and S0536 (carboplatin-paclitaxel-Cetuximab-bevacizumab) was analyzed for KRAS mutations by micro-dissection/sequencing and/or Scorpion-ARMS (DxS LTD). Results: For S0342, 45 archival tissues and 90 plasma specimens were analyzed. Combined, KRAS mutations were detected in 24% of pts. No differences between mutant and WT tumors were obser...