Erlotinib: an EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment

Schettino, Clorinda; Bareschino, Maria Anna; Ricci, Vincenzo; Ciardiello, Fortunato

doi:10.1586/17476348.2.2.167

Cited by 61 publications

(44 citation statements)

References 59 publications

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“…For the 5-FU with cisplatin study, 500 μM 5-FU and 30 μM cisplatin were used for KYSE150, while 25 μM 5-FU and 5 μM cisplatin were used for SLMT. To study the effect on EGFR and ERK activation on PD-L1 expression, 500 μM erlotinib was used to inhibit EGFR activation [13], and 10 μM AZD6244 was used to inhibit the MEK pathway [14] in both cell lines.…”

Section: Methodsmentioning

confidence: 99%

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

Tao

et al. 2018

Translational Oncology

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The current study reveals the clinicopathological association of PD-L1 in Hong Kong esophageal squamous cell carcinoma (ESCC) patients and the differential regulation of PD-L1 by standard first-line chemotherapy in ESCC. Immunohistochemical analysis of tissue microarray data from 84 Hong Kong ESCC patients shows that PD-L1 was expressed in 21% of the tumors. Positive PD-L1 staining was significantly associated with later disease stage (stages III and IV) (P value = .0379) and lymph node metastasis (P value = .0466) in the Hong Kong cohort. Furthermore, PD-L1 expression was significantly induced in ESCC cell lines after standard chemotherapy treatments, along with EGFR and ERK activation in both in vitro studies and the in vivo esophageal orthotopic model. The endogenous expression of PD-L1 was reduced by treatment with an EGFR inhibitor (erlotinib) or by the knockdown of EGFR. Moreover, the upregulation of PD-L1 by chemotherapy was also attenuated by the treatment with erlotinib and a MAPK/MEK inhibitor (AZD6244), suggesting that PD-L1 is regulated by the EGFR/ERK pathway in ESCC. The regulation of PD-L1 by the EGFR pathway was further supported by the correlation of PD-L1 and EGFR expression observed in the commercially available tissue microarray set (P value = .028). Taken together, the current study was the first to demonstrate the upregulation of PD-L1 by chemotherapy in ESCC and its regulation through the EGFR/ERK pathway. The results suggest the potential usefulness of combined conventional chemotherapy together with anti–PD-L1 immunotherapy to achieve better treatment outcome.

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Section: Methodsmentioning

confidence: 99%

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

Tao

et al. 2018

Translational Oncology

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“…Co-treatment with the potent CYP3A4 inhibitor ketoconazole increased erlotinib AUC by two-thirds. Additionally, pre-or co-treatment with a CYP3A4 inducer such as rifampicin, phenytoin or barbiturates increased erlotinib clearance threefold and reduced AUC two-thirds [37]. A single-dose study in healthy subjects confirmed that AUC ?…”

Section: Discussionmentioning

confidence: 76%

Pharmacokinetic Properties of Two Erlotinib 150 mg Formulations with a Genetic Effect Evaluation in Healthy Korean Subjects

Choi

Jeon

et al. 2014

Clin Drug Investig

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This study suggests that the test and reference formulations of 150 mg erlotinib have similar pharmacokinetic characteristics. Both had no major safety issues and were well-tolerated. The test formulation met the regulatory criteria for assuming bioequivalence to the reference formulation for both AUCt and C max. The additional genetic analysis demonstrated that the major metabolic enzymes of erlotinib did not significantly affect erlotinib metabolism, with the exception of CYP1A2*1M.

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“…Tarceva® (erlotinib) is approved as a first-line and maintenance treatment, and 2nd- or 3rd-line treatment for advanced-stage non-small cell lung cancer (NSCLC). It is an orally administered reversible tyrosine kinase inhibitor (TKI) targeting the EGF receptor, that is up-regulated in the majority of lung, colorectal, and head and neck cancers (3). However, EGFR activation is also required for active epithelial magnesium (Mg)-absorption that is mediated by the transient receptor potential melastatin 6 (TRPM6) channel in the kidney and colon (4).…”

Section: Introductionmentioning

confidence: 99%

EGFR-TKI, Erlotinib, Causes Hypomagnesemia, Oxidative Stress, and Cardiac Dysfunction

Mak

Kramer

Chmielinska

et al. 2015

Journal of Cardiovascular Pharmacology

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To determine whether the EGFR tyrosine kinase inhibitor, erlotinib may cause hypomagnesemia, inflammation and cardiac stress, erlotinib was administered to rats (10 mg/kg/day) for 9 weeks. Plasma magnesium decreased progressively between 3-9 weeks (-9 to -26%). Modest increases in plasma substance P (SP) occurred at 3 (+27%) and 9 (+25%) weeks. Neutrophil superoxide-generating activity increased 3-fold, and plasma 8-isoprostane rose 210%, along with noticeable appearance of cardiac peri-vascular nitrotyrosine. The neurokinin-1 (NK-1) receptor antagonist, aprepitant (2 mg/kg/day), attenuated erlotinib-induced hypomagnesemia up to 42%; reduced circulating SP, suppressed neutrophil superoxide activity and 8-isoprostane elevations; cardiac nitrotyrosine was diminished. Echocardiography revealed mild to moderately decreased left ventricular ejection fraction (-11%) and % fractional shortening (-17%) by 7 weeks of erlotinib treatment, and significant reduction (-17.5%) in mitral valve E/A ratio at week 9, indicative of systolic and early diastolic dysfunction. Mild thinning of the left ventricular posterior wall suggested early dilated cardiomyopathy. Aprepitant completely prevented the erlotinib-induced systolic and diastolic dysfunction, and partially attenuated the anatomical changes. Thus, chronic erlotinib treatment does induce moderate hypomagnesemia, triggering SP-mediated oxidative/inflammation stress, and mild to moderate cardiac dysfunction, which can largely be corrected by administration of the SP receptor blocker.

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Erlotinib: an EGF receptor tyrosine kinase inhibitor in non-small-cell lung cancer treatment

Cited by 61 publications

References 59 publications

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

Chemotherapeutic Treatments Increase PD-L1 Expression in Esophageal Squamous Cell Carcinoma through EGFR/ERK Activation

Pharmacokinetic Properties of Two Erlotinib 150 mg Formulations with a Genetic Effect Evaluation in Healthy Korean Subjects

EGFR-TKI, Erlotinib, Causes Hypomagnesemia, Oxidative Stress, and Cardiac Dysfunction

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