Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer

Miyamoto, Yuji; Suyama, Koichi; Baba, Hideo

doi:10.3390/ijms18040752

Cited by 90 publications

(57 citation statements)

References 99 publications

(113 reference statements)

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“…The Ras/PI3K/PTEN/AKT/mTOR pathway mediates EGFR downstream signaling, playing a key role in the regulation of proteins critical for protein translation [37]. Activation of EGFR and the Ras/PI3K/PTEN/AKT/mTOR signaling pathway also triggers angiogenesis by upregulating HIF-1α and inducing the expression of VEGF [38].…”

Section: Discussionmentioning

confidence: 99%

Local Delivery of Gemcitabine Inhibits Pancreatic and Cholangiocarcinoma Tumor Growth by Promoting Epidermal Growth Factor Receptor Degradation

Jang

Fang

Baek

et al. 2020

IJMS

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Gemcitabine is clinically used to treat certain types of cancers, including pancreatic and biliary cancer. We investigated the signal transduction pathways underlying the local antitumor effects of gemcitabine-eluting membranes (GEMs) implanted in pancreatic/biliary tumor-bearing nude mice. Here, we report that GEMs increased the E3 ubiquitin ligase c-CBL protein level, leading to degradation of epidermal growth factor receptor (EGFR) in SCK and PANC-1 cells. GEMs decreased the RAS and PI3K protein levels, leading to a reduction in the protein levels of active forms of downstream signaling molecules, including PDK, AKT, and GSK3β. GEM reduced proliferation of cancer cells by upregulating cell cycle arrest proteins, particularly p53 and p21, and downregulating cyclin D1 and cyclin B. Moreover, GEMs reduced the levels of proangiogenic factors, including VEGF, VEGFR2, CD31, and HIF-1α, and inhibited tumor cell migration and invasion by inducing the expression of E-cadherin and reducing that of N-cadherin, snail, and vimentin. We demonstrated that local delivery of gemcitabine using GEM implants inhibited tumor cell growth by promoting c-CBL-mediated degradation of EGFR and inhibiting the proliferation, angiogenesis, and epithelial–mesenchymal transition of pancreatic/biliary tumors. Use of gemcitabine-eluting stents can improve stent patency by inhibiting the ingrowth of malignant biliary obstructions.

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Section: Discussionmentioning

confidence: 99%

Local Delivery of Gemcitabine Inhibits Pancreatic and Cholangiocarcinoma Tumor Growth by Promoting Epidermal Growth Factor Receptor Degradation

Jang

Fang

Baek

et al. 2020

IJMS

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“…WNT and MAPK signaling are typically active in colorectal cancer and drive tumor progression . Although targeting WNT appears to be difficult, MAPK signaling can be inhibited by antibodies against EGFR or by MEK inhibitors that block signal transduction and thus may slow tumor progression . Combining such treatment with chemotherapy may increase response rates even further, although, based on other data, the superiority of such combinations remains a matter of debate .…”

Section: Introductionmentioning

confidence: 99%

In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer

et al. 2019

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Patients with advanced colorectal cancer often are treated with systemic cytotoxic therapy using fluorouracil (5‐FU), oxaliplatin, irinotecan, and FOLFOX or FOLFIRI combination protocols. Additionally, signaling pathways that are active in colorectal cancer can be therapeutically targeted. Herein, we examined whether chemotherapy impacts on WNT, MAPK and NOTCH signaling pathways in xenograft models of colon cancer. Furthermore, we tested whether combining chemotherapy with MAPK and NOTCH inhibition has superior therapeutic effects. We show that colon cancer cells with high WNT, MAPK and NOTCH activity are variably affected but generally persist in xenograft tumors under different chemotherapeutic regimens, indicating limited effects of cytotoxic therapy on oncogenic signaling pathways. Although these results provided a rationale to additionally target pathway activity, we found no significant increase in therapy response when combining MAPK and NOTCH inhibition with fluorouracil chemotherapy. We attribute this finding to a decrease in tumor cell proliferation upon MAPK and NOTCH inhibition, resulting in reduced effectiveness of cytotoxic treatment. Therapeutic benefits of combining chemotherapy with targeting of oncogenic signaling pathways must therefore be critically evaluated for patients with colorectal cancer.

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“…Applications of precision medicine technologies include using blood-based protein markers to predict patient prognosis and monitor patients for recurrence, [3][4][5][6] identifying patients who are at a high risk for cancer using germline genetic tests, [7][8][9] and analyzing molecular markers in tumor tissue to characterize patients' risk of recurrence and tumor susceptibility to specific targeted therapies. [10][11][12][13] Precision medicine has enormous potential to improve cancer care. However, there are many unanswered questions about the impact of precision medicine on survival, quality of life, patient costs, health system costs, and health disparities in real-world clinical settings (as opposed to in clinical trials).…”

Section: Introductionmentioning

confidence: 99%

Clinical Molecular Marker Testing Data Capture to Promote Precision Medicine Research Within the Cancer Research Network

Burnett‐Hartman

Udaltsova

Kushi

et al. 2019

JCO Clinical Cancer Informatics

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PURPOSE To evaluate health care systems for the availability of population-level data on the frequency of use and results of clinical molecular marker tests to inform precision cancer care. METHODS We assessed cancer-related molecular marker test data availability across 12 US health care systems in the Cancer Research Network. Overall, these systems provide care to a diverse population of more than 12 million people in the United States. We performed qualitative analyses of test data availability for five blood-based protein, nine germline, and 14 tissue-based tumor marker tests in each health care system’s electronic health record and tumor registry using key informants, test code lists, and manual review of data types and output. We then performed quantitative analyses to estimate the proportion of patients with cancer with test utilization data and results for specific molecular marker tests. RESULTS Health systems were able to systematically capture population-level data on all five blood protein markers, six of 14 tissue-based tumor markers, and none of the nine germline markers. Successful, systematic data capture was achievable for tests with electronic data feeds for test results (blood protein markers) or through prior manual abstraction by tumor registrars (select tumor-based markers). For test results stored in scanned image files (particularly germline and tumor marker tests), information on which test was performed and test results was not readily accessible in an electronic format. CONCLUSION Even in health care systems with sophisticated electronic health records, there were few codified data elements available for evaluating precision cancer medicine test use and results at the population level. Health care organizations should establish standards for electronic reporting of precision medicine tests to expedite cancer research and facilitate the implementation of precision medicine approaches.

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Recent Advances in Targeting the EGFR Signaling Pathway for the Treatment of Metastatic Colorectal Cancer

Cited by 90 publications

References 99 publications

Local Delivery of Gemcitabine Inhibits Pancreatic and Cholangiocarcinoma Tumor Growth by Promoting Epidermal Growth Factor Receptor Degradation

Local Delivery of Gemcitabine Inhibits Pancreatic and Cholangiocarcinoma Tumor Growth by Promoting Epidermal Growth Factor Receptor Degradation

In vivo effects of chemotherapy on oncogenic pathways in colorectal cancer

Clinical Molecular Marker Testing Data Capture to Promote Precision Medicine Research Within the Cancer Research Network

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