Targeted therapies in medical oncology: successes, failures and next steps

Mallarkey, Gordon; Coombes, R. Charles

doi:10.1177/1758834012467829

Cited by 10 publications

(7 citation statements)

References 28 publications

(64 reference statements)

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“…In clinical trials with unselected patients, Erlotinib has shown moderate effects in Phase II, whereas Gefitinib and Cetuximab have provided only disappointing results in advanced stage HCC patients 2 . Moreover, the SEARCH trial, the only Phase III study performed, was unable to show survival improvement with Erlotinib in advanced stage HCC 24 . Therefore, a better understanding of the mechanisms whereby EGFR signaling influences HCC progression is needed.…”

Section: Introductionmentioning

confidence: 99%

EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation

et al. 2014

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Hepatocellular carcinoma (HCC) is a frequent cancer with limited treatment options and poor prognosis. Tumorigenesis has been linked with macrophage-mediated chronic inflammation and diverse signaling pathways including the Epidermal Growth Factor Receptor (EGFR) pathway. The precise role of EGFR in HCC is unknown, and EGFR-inhibitors have shown disappointing clinical results. Here we discover that EGFR is expressed in liver macrophages in both human HCC and in a mouse HCC model. Mice lacking EGFR in macrophages show impaired hepatocarcinogenesis, whereas mice lacking EGFR in hepatocytes unexpectedly develop more HCC due to increased hepatocyte damage and compensatory proliferation. Mechanistically, following IL-1 stimulation, EGFR is required in liver macrophages to transcriptionally induce IL-6, which triggers hepatocyte proliferation and HCC. Importantly, the presence of EGFR-positive liver macrophages in HCC-patients is associated with poor survival. This study demonstrates a tumor-promoting mechanism for EGFR in non-tumor cells, which could lead to more effective precision medicine strategies.

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Section: Introductionmentioning

confidence: 99%

EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation

et al. 2014

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“…Moreover, EGFR is overexpressed in 40% to 70% of human HCCs (10). Still, EGFR inhibitors (cetuximab, gefitinib, and erlotinib) did not show significant efficacy in unselected patients with advanced HCC in clinical trials (11,12). Therefore, a better understanding of the regulation of EGFR signaling is critical for the therapy of cancer in general and HCC in particular.…”

Section: Introductionmentioning

confidence: 99%

CD317 Activates EGFR by Regulating Its Association with Lipid Rafts

Zhang

Chen

et al. 2019

Cancer Research

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EGFR regulates various fundamental cellular processes, and its constitutive activation is a common driver for cancer. Anti-EGFR therapies have shown benefit in cancer patients, yet drug resistance almost inevitably develops, emphasizing the need for a better understanding of the mechanisms that govern EGFR activation. Here we report that CD317, a surface molecule with a unique topology, activated EGFR in hepatocellular carcinoma (HCC) cells by regulating its localization on the plasma membrane. CD317 was upregulated in HCC cells, promoting cell-cycle progression and enhancing tumorigenic potential in a manner dependent on EGFR. Mechanistically, CD317 associated with lipid rafts and released EGFR from these ordered membrane domains, facilitating the activation of EGFR and the initiation of downstream signaling pathways, including the Ras-Raf-MEK-ERK and JAK-STAT pathways. Moreover, in HCC mouse models and patient samples, upregulation of CD317 correlated with EGFR activation. These results reveal a previously unrecognized mode of regulation for EGFR and suggest CD317 as an alternative target for treating EGFR-driven malignancies.Significance: Activation of EGFR by CD317 in hepatocellular carcinoma cells suggests CD317 as an alternative target for treating EGFR-dependent tumors.

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“…6 Elevated expression of the EGFR ligands has also been reported in the preneoplastic lesions of liver tissues, indicating its potential role in hepatocarcinogenesis. Although EGFR antagonists have an effect on cell malignancy in human HCC cells and in animal HCC model, several clinical trials was unable to show significant survival improvement with gefitinib, cetuximab, 7 or erlotinib 8 in HCC patients. These data reinforced the importance of better understanding the mechanisms and identifying potential intracellular effectors whereby EGFR signaling influences HCC progression.…”

mentioning

confidence: 99%

Choline Kinase α Mediates Interactions Between the Epidermal Growth Factor Receptor and Mechanistic Target of Rapamycin Complex 2 in Hepatocellular Carcinoma Cells to Promote Drug Resistance and Xenograft Tumor Progression

Lin

et al. 2017

Gastroenterology

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We found levels of CHKA to be increased in human HCCs compared to nontumor tissues, and increased expression to be associated with tumor aggressiveness and reduced survival times of patients. Overexpression of CHKA in HCC cell lines increased their invasiveness, resistance to EGFR inhibitors, and ability to form metastatic tumors in mice by promoting interaction of EGFR with mechanistic target of rapamycin complex 2.

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Targeted therapies in medical oncology: successes, failures and next steps

Cited by 10 publications

References 28 publications

EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation

EGFR has a tumour-promoting role in liver macrophages during hepatocellular carcinoma formation

CD317 Activates EGFR by Regulating Its Association with Lipid Rafts

Choline Kinase α Mediates Interactions Between the Epidermal Growth Factor Receptor and Mechanistic Target of Rapamycin Complex 2 in Hepatocellular Carcinoma Cells to Promote Drug Resistance and Xenograft Tumor Progression

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