Epidermal Growth Factor Receptor cooperates with Src Family Kinases in acquired resistance to cetuximab

Wheeler, Deric L.; Iida, Mari; Kruser, Tim J.; Nechrebecki, Meghan; Dunn, Emily F.; Armstrong, Eric A.; Huang, Shyhmin; Harari, Paul M.

doi:10.4161/cbt.8.8.7903

Cited by 136 publications

(109 citation statements)

References 27 publications

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“…The finding that Src family kinases are sufficient to modify EGFR dependence is in line with considerable evidence linking EGFR activity with this family: c-Src itself has been characterized extensively with respect to its cooperative relationship with EGFR (27), and the introduction of dominant-active c-Src can reduce the inhibitory effects of erlotinib in head and neck squamous cell carcinoma models (28). Src family kinase activation has been observed in cetuximab-resistant colorectal adenocarcinoma and NSCLC squamous cell carcinoma in vitro models (29,30), and it has been reported that CRIPTO1-mediated EGFR TKI resistance in NSCLC is Src-dependent (31). Furthermore, a recent report described increased expression and activation of Src, mediated by integrin activation, in EGFR TKI-resistant lung adenocarcinoma models (32).…”

Section: Discussionmentioning

confidence: 58%

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Sharifnia

Rusu

Piccioni

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Lung adenocarcinomas harboring activating mutations in the epidermal growth factor receptor (EGFR) represent a common molecular subset of non-small cell lung cancer (NSCLC) cases. EGFR mutations predict sensitivity to EGFR tyrosine kinase inhibitors (TKIs) and thus represent a dependency in NSCLCs harboring these alterations, but the genetic basis of EGFR dependence is not fully understood. Here, we applied an unbiased, ORF-based screen to identify genetic modifiers of EGFR dependence in EGFR-mutant NSCLC cells. This approach identified 18 kinase and kinase-related genes whose overexpression can substitute for EGFR in EGFRdependent PC9 cells, and these genes include seven of nine Src family kinase genes, FGFR1, FGFR2, ITK, NTRK1, NTRK2, MOS, MST1R, and RAF1. A subset of these genes can complement loss of EGFR activity across multiple EGFR-dependent models. Unbiased gene-expression profiling of cells overexpressing EGFR bypass genes, together with targeted validation studies, reveals EGFRindependent activation of the MEK-ERK and phosphoinositide 3-kinase (PI3K)-AKT pathways. Combined inhibition of PI3K-mTOR and MEK restores EGFR dependence in cells expressing each of the 18 EGFR bypass genes. Together, these data uncover a broad spectrum of kinases capable of overcoming dependence on EGFR and underscore their convergence on the PI3K-AKT and MEK-ERK signaling axes in sustaining EGFR-independent survival. epidermal growth factor receptor | non-small cell lung cancer | ORF

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Section: Discussionmentioning

confidence: 58%

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Sharifnia

Rusu

Piccioni

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Several mechanisms of resistance to cetuximab have been described. Western blot and immunofluorescence analysis showed that the expression level and localization of EGFR in SAS cells were similar to those of cetuximab-sensitive cell lines, indicating that neither the expression and activity level of EGFR (39), nor inappropriate cellular distribution of EGFR (28,40) was probable cause of the drug resistance shown by SAS cells. However, the fact that phosphorylated EGFR is expressed by SAS cells suggests that EGFR is indeed stimulated by a ligand in such cells and plays a role in the regulation of a function other than growth, which may in turn be affected by cetuximab.…”

Section: Discussionmentioning

confidence: 99%

“…First, resistance may develop via constitutive activation of growth caused by changes in effectors of the EGFR signal transduction pathway (23)(24)(25)(26). Second, proliferation may be stimulated by activation of receptors other than EGFR (27)(28)(29)(30). However, the detailed features of cetuximab remain elusive.…”

Section: Introductionmentioning

confidence: 99%

Resistance of oral squamous cell carcinoma cells to cetuximab is associated with EGFR insensitivity and enhanced stem cell-like potency

et al. 2014

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Abstract. Cetuximab, a specific anti-epidermal growth factor receptor (EGFR) monoclonal antibody, is used in cancer treatment. Although development of resistance to cetuximab is well recognized, the underlying mechanisms remain unclear.In the present study, we characterized cetuximab-resistant oral squamous cell carcinoma (OSCC) cell lines. The human OSCC cell lines HSC3, HSC4 and SAS were used in the present study. Effects of inhibitors including cetuximab on growth in cells were assessed by MTT assays. Southern blotting and immunofluorescence analysis were performed to examine protein expression and localization. Sphere formation was used to characterize stem cell-like properties. Floating aggregation culture was used for anchorage-independent growth. Cetuximab inhibited proliferation of HSC3 and HSC4 cells, but not SAS cells. Proliferation of all three cell lines was inhibited by the EGFR/ErbB2/ErbB4 inhibitor II. The EGFR inhibitor AG1478 strongly inhibited HSC3 and HSC4 proliferation, but that of SAS cells only moderately. EGFR proteins were localized on cell surface and phosphorylated in all three cell lines. SAS cells could proliferate in serum-free monolayer culture and formed spheres from single cells in floating culture. HSC3 and HSC4 could not proliferate under serum-free culture conditions and could not form spheres. Growth of SAS spheres required serum, and was inhibited by both AG1478 and cetuximab. Thus, cetuximab-resistant SAS cells not only engaged in EGFR-independent growth but also exhibited stem cell-like properties. However, growth was EGFR-dependent in aggregation culture, and the SAS cell aggregates became cetuximab-sensitive. This suggests that cetuximab sensitivity is not only cell-type-dependent but is also affected by the growth microenvironment.

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“…In this study, Wheeler et al used cetuximab-resistant clones derived from the NSCLC NCI-H226 cell line. 184 Cetuximab-resistant cells demonstrated a robust increase in SFK activity compared to sensitive parental control cells, possibly due to the steady state increase of EGFR in resistant lines. In addition, cetuximab-resistant cell lines had high AKT activity.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, cetuximab-resistant cells had increased SFK expression. 184 Based on this knowledge, researchers postulated that SFKs may influence nuclear EGFR and modulate cetuximab resistance. Using the pan-SFK inhibitor, Dasatinib, a 2.7-5.5-fold decrease in nuclear EGFR was detected with a significant increase in surface associated EGFR levels measured via flow cytometry.…”

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confidence: 99%

Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab

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Iida

Wheeler

2011

Cancer Biology & Therapy

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The epidermal growth factor receptor (eGFR) is a receptor tyrosine kinase belonging to the HeR family of receptor tyrosine kinases. Receptor activation upon ligand binding leads to down stream activation of the Pi3K/AKT, RAs/RAF/MeK/ eRK and PLCγ/PKC pathways that influence cell proliferation, survival and the metastatic potential of tumor cells. increased activation by gene amplification, protein overexpression or mutations of the eGFR has been identified as an etiological factor in a number of human epithelial cancers (e.g., NsCLC, CRC, glioblastoma and breast cancer). Therefore, targeting the eGFR has been intensely pursued as a cancer treatment strategy over the last two decades. To date, five eGFR inhibitors, including three small molecule tyrosine kinase inhibitors (TKis) and two monoclonal antibodies have gained FdA approval for use in oncology. Both approaches to targeting the eGFR have shown clinical promise and the anti-eGFR antibody cetuximab is used to treat HNsCC and CRC. despite clinical gains arising from use of cetuximab, both intrinsic resistance and the development of acquired resistance are now well recognized. in this review we focus on the biology of the eGFR, the role of eGFR in human cancer, the development of

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Epidermal Growth Factor Receptor cooperates with Src Family Kinases in acquired resistance to cetuximab

Cited by 136 publications

References 27 publications

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Genetic modifiers of EGFR dependence in non-small cell lung cancer

Resistance of oral squamous cell carcinoma cells to cetuximab is associated with EGFR insensitivity and enhanced stem cell-like potency

Molecular mechanisms of resistance to the EGFR monoclonal antibody cetuximab

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