Epidermal Growth Factor Receptor (EGFR) Ubiquitination as a Mechanism of Acquired Resistance Escaping Treatment by the Anti-EGFR Monoclonal Antibody Cetuximab
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]
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Deregulation of EGFR ubiquitination affects receptor recycling and expression at the cell membrane.
“deregulation of EGFR ubiquitination which affects receptor recycling and expression at the cell membrane [128]”
From Primary and acquired resistance to EGFR-targeted therapies in colorectal cancer: impact on future treatment strategies (2014) · cites this paper as [128]
Cites
Nagata, Y., Lan, K.-H., Zhou, X., Tan, M., Esteva, F. J., Sahin, A. A., Klos, K. S., Li, P., Monia, B. P., Nguyen, N. T., et al. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.06.022 · Cited by 1,858 · see citing works
The EGF receptor family as targets for cancer therapy
Mendelsohn, J. M., & Baselga, J. M. (2000) · Oncogene · doi:10.1038/sj.onc.1204082 · Cited by 1,341 · see citing works
Self-citationStatus of Epidermal Growth Factor Receptor Antagonists in the Biology and Treatment of Cancer
Mendelsohn, J. M., & Baselga, J. M. (2003) · Journal of Clinical Oncology · doi:10.1200/jco.2003.01.504 · Cited by 1,257 · see citing works
Self-citationPhosphorylation and Regulation of Raf by Akt (Protein Kinase B)
Zimmermann, S., & Moelling, K. (1999) · Science · doi:10.1126/science.286.5445.1741 · Cited by 1,088 · see citing works
Src family kinases, key regulators of signal transduction
Parsons, S. J., & Parsons, J. T. (2004) · Oncogene · doi:10.1038/sj.onc.1208160 · Cited by 942 · see citing works
Differentiation Stage-Specific Inhibition of the Raf-MEK-ERK Pathway by Akt
Rommel, C., Clarke, B. A., Zimmermann, S., Nuñez, L., Rossman, R., Reid, K., Moelling, K., Yancopoulos, G. D., & Glass, D. J. (1999) · Science · doi:10.1126/science.286.5445.1738 · Cited by 759 · see citing works
Diversity and frequency of epidermal growth factor receptor mutations in human glioblastomas.
Frederick, L. A., Wang, X. Y., Eley, G. D., & James, C. D. (2000) · PubMed · Cited by 661 · see citing works
Biscardi, J. S., Maa, M.-C., Tice, D. A., Cox, M. E., Leu, T.-H., & Parsons, S. J. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.12.8335 · Cited by 649 · see citing works
c-Src and cooperating partners in human cancer
Ishizawar, R., & Parsons, S. J. (2004) · Cancer Cell · doi:10.1016/j.ccr.2004.09.001 · Cited by 617 · see citing works
Viloria‐Petit, A., Crombet, T., Jothy, S., Hicklin, D. J., Böhlen, P., Schlaeppi, J.-M., Rak, J. W., & Kerbel, R. S. (2001) · PubMed · Cited by 558 · see citing works
Mechanism of biological synergy between cellular Src and epidermal growth factor receptor
Tice, D. A., Biscardi, J. S., Nickles, A. L., & Parsons, S. J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.4.1415 · Cited by 472 · see citing works
Fan, Z., Baselga, J., Masui, H., et al. (1993) · PubMed · Cited by 431 · see citing works
Self-citationWu, X., Fan, Z., Masui, H., Rosen, N. X., & Mendelsohn, J. M. (1995) · Journal of Clinical Investigation · doi:10.1172/jci117871 · Cited by 381 · see citing works
Self-citationCiardiello, F., Bianco, R., Damiano, V., Fontanini, G., Caputo, R., Pomatico, G., Placido, S. D., Bianco, A. R., Mendelsohn, J. M., & Tortora, G. (2000) · PubMed · Cited by 379 · see citing works
Self-citationCiardiello, F., Bianco, R., Caputo, R., Caputo, R., Damiano, V., Troiani, T., Melisi, D., De Vita, F., De Placido, S., Bianco, A. R., et al. (2004) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-1100-03 · Cited by 347 · see citing works
Ciardiello, F., Bianco, R., Damiano, V., Lorenzo, S. D., Pepe, S., Placido, S. D., Fan, Z., Mendelsohn, J. M., Bianco, A. R., & Tortora, G. (1999) · PubMed · Cited by 332 · see citing works
Self-citationA tail of two src's: Mutatis mutandis
Hunter, T. R. (1987) · Cell · doi:10.1016/0092-8674(87)90745-8 · Cited by 282 · see citing works
Soderquist, A. M., & Carpenter, G. (1984) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)90787-8 · Cited by 233 · see citing works
Wu, X., Rubin, M., Fan, Z., DeBlasio, T., Soos, T. J., Koff, A., & Mendelsohn, J. M. (1996) · PubMed · Cited by 228 · see citing works
Self-citationThien, C. B. F., Walker, F., & Langdon, W. Y. (2001) · Molecular Cell · doi:10.1016/s1097-2765(01)00183-6 · Cited by 177 · see citing works
c-SRC Phosphorylates Epidermal Growth Factor Receptor on Tyrosine 845
Sato, K., Sato, A., Aoto, M., & Fukami, Y. (1995) · Biochemical and Biophysical Research Communications · doi:10.1006/bbrc.1995.2574 · Cited by 139 · see citing works
Bao, J., Gur, G., & Yarden, Y. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0437945100 · Cited by 136 · see citing works
Liu, B., Fang, M., Schmidt, M., Lü, Y., Mendelsohn, J. M., & Fan, Z. (2000) · British Journal of Cancer · doi:10.1054/bjoc.2000.1201 · Cited by 125 · see citing works
Self-citationLiu, B., Fang, M., Lü, Y., Mendelsohn, J. M., & Fan, Z. (2001) · Oncogene · doi:10.1038/sj.onc.1204277 · Cited by 105 · see citing works
Self-citationBoerner, J. L., Biscardi, J. S., Silva, C. M., & Parsons, S. J. (2005) · Molecular Carcinogenesis · doi:10.1002/mc.20138 · Cited by 74 · see citing works
Sato, K., Nagao, T., Iwasaki, T., Nishihira, Y., & Fukami, Y. (2003) · Genes to Cells · doi:10.1046/j.1356-9597.2003.00691.x · Cited by 73 · see citing works
Expression of an altered epidermal growth factor receptor by human glioblastoma cells.
Steck, P. A., Lee, P., Hung, M., et al. (1988) · PubMed · Cited by 66 · see citing works
Liu, B., & Fan, Z. (2001) · Oncogene · doi:10.1038/sj.onc.1204490 · Cited by 41 · see citing works
Self-citationCiesielski, M. J., & Fenstermaker, R. A. (2000) · Oncogene · doi:10.1038/sj.onc.1203409 · Cited by 40 · see citing works
Fenstermaker, R. A., & Ciesielski, M. J. (2000) · Oncogene · doi:10.1038/sj.onc.1203802 · Cited by 26 · see citing works
Panneerselvam, K., Kanakaraj, P., Raj, S., et al. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.0951g.x · Cited by 12 · see citing works
Panneerselvam, K., Kanakaraj, P., Raj, S., et al. (1995) · European Journal of Biochemistry · doi:10.1111/j.1432-1033.1995.tb20641.x · Cited by 11 · see citing works
New drug to treat most common lung cancer.
(2005) · PubMed · Cited by 2 · see citing works
Speedy Approvals for New Cancer Treatments
(2003) · PsycEXTRA Dataset · doi:10.1037/e542942006-008 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Amado, R. G., Wolf, M., Peeters, M., Van Cutsem, E., Siena, S., Freeman, D. J., Juan, T., Sikorski, R., Suggs, S., Radinsky, R., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2007.14.7116 · Cited by 3,207 · see citing works
The molecular evolution of acquired resistance to targeted EGFR blockade in colorectal cancers
Diaz Jr, L. A., Williams, R. T., Wu, J., Kinde, I., Hecht, J. R., Berlin, J., Allen, B., Bozic, I., Reiter, J. G., Nowak, M. A., et al. (2012) · Nature · doi:10.1038/nature11219 · Cited by 1,713 · see citing works
Di Nicolantonio, F., Martini, M., Molinari, F., Sartore-Bianchi, A., Arena, S., Saletti, P., De Dosso, S., Mazzucchelli, L., Frattini, M., Siena, S., et al. (2008) · Journal of Clinical Oncology · doi:10.1200/jco.2008.18.0786 · Cited by 1,591 · see citing works
Understanding resistance to EGFR inhibitors—impact on future treatment strategies
Wheeler, D. L., Dunn, E. F., & Harari, P. M. (2010) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2010.97 · Cited by 683 · see citing works
Bardelli, A., Corso, S., Bertotti, A., Hobor, S., Valtorta, E., Siravegna, G., Sartore-Bianchi, A., Scala, E., Cassingena, A., Zecchin, D., et al. (2013) · Cancer Discovery · doi:10.1158/2159-8290.cd-12-0558 · Cited by 657 · see citing works
Met receptor contributes to trastuzumab resistance of Her2-overexpressing breast cancer cells
Shattuck, D. L., Miller, J. K., Carraway, K. L., & Sweeney, C. (2008) · Cancer Research · doi:10.1158/0008-5472.can-07-5962 · Cited by 473 · see citing works
The Role of Src in Solid Tumors
Wheeler, D. L., Iida, M., & Dunn, E. F. (2009) · The Oncologist · doi:10.1634/theoncologist.2009-0009 · Cited by 346 · see citing works
Li, X., & Fan, Z. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0157 · Cited by 179 · see citing works
Self-citationKopetz, S., Lesslie, D. P., Dallas, N. A., Park, S. I., Johnson, M., Parikh, N. U., Kim, M. P., Abbruzzese, J. L., Ellis, L. M., Chandra, J., et al. (2009) · Cancer Research · doi:10.1158/0008-5472.can-08-2246 · Cited by 160 · see citing works
Wheeler, D. L., Iida, M., Kruser, T. J., Nechrebecki, M. M., Dunn, E. F., Armstrong, E. A., Huang, S., & Harari, P. M. (2009) · Cancer Biology & Therapy · doi:10.4161/cbt.8.8.7903 · Cited by 157 · see citing works
Leto, S. M., & Trusolino, L. (2014) · Journal of Molecular Medicine · doi:10.1007/s00109-014-1161-2 · Cited by 87 · see citing works
Koustas, E., Karamouzis, M. V., Mihailidou, C., Schizas, D., & Papavassiliou, A. G. (2017) · Cancer Letters · doi:10.1016/j.canlet.2017.03.023 · Cited by 79 · see citing works
Parseghian, C. M., Parikh, N. U., Wu, J. Y., Jiang, Z.-Q., Henderson, L., Tian, F., Pastor, B., Ychou, M., Raghav, K., Dasari, A., et al. (2017) · Clinical Cancer Research · doi:10.1158/1078-0432.ccr-16-3138 · Cited by 67 · see citing works
Oliveras‐Ferraros, C., Vazquez‐Martin, A., Cufí, S., Queralt, B., Báez, L., Guardeño, R., Hernández‐Yagüe, X., Martin‐Castillo, B., Brunet, J., & Menendez, J. A. (2011) · Journal of Cellular Biochemistry · doi:10.1002/jcb.22952 · Cited by 47 · see citing works
Knickelbein, K., Tong, J., Chen, D., Wang, Y.-J., Misale, S., Bardelli, A., Yu, J., & Zhang, L. (2018) · Oncogene · doi:10.1038/s41388-018-0289-x · Cited by 33 · see citing works
- Authors
- Lu, Y., Li, X., Liang, K., Luwor, R., Siddik, Z. H., Mills, G. B., Mendelsohn, J., & Fan, Z.
- Affiliations
- 1Experimental Therapeutics and Departments of
- The University of Texas Health Science Center at Houston (US)
- The University of Texas MD Anderson Cancer Center (US)
- Venue
- Cancer Research
- Published
- 2007-09-01
- Volume
- 67
- Issue
- 17
- Pages
- 8240-8247
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2107693250
- Cited by
- 170
- References
- 34
- Citations by year
- 2026: 5 · 2025: 3 · 2024: 4 · 2023: 7 · 2022: 5 · 2021: 5 · 2020: 7 · 2019: 7 · 2018: 6 · 2017: 4 · 2016: 8 · 2015: 13 · 2014: 20 · 2013: 9 · 2012: 10
- FWCI
- 7.74
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › HER2/EGFR in Cancer Research
- Health Sciences › Medicine › Oncology › Colorectal Cancer Treatments and Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Keywords
- cetuximab, EGFR, acquired drug resistance, ubiquitination, EGFR degradation, Src kinase, CBL, colorectal cancer, EGF signaling, Akt, ERK, apoptosis, monoclonal antibody therapy
- MeSH terms
- Cetuximab, Adenocarcinoma, Antibodies, Monoclonal, Humans, Protein Processing, Post-Translational, Tumor Cells, Cultured, Colorectal Neoplasms, Signal Transduction, Drug Resistance, Neoplasm, src-Family Kinases, Ubiquitin, Antibodies, Monoclonal, Humanized, ErbB Receptors
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