Inetetamab combined with S-1 and oxaliplatin as first-line treatment for human epidermal growth factor receptor 2-positive gastric cancer

BACKGROUND Patients with human epidermal growth factor receptor 2(HER2)-positive advanced gastric cancer have poor outcomes.Trastuzumab combined with chemotherapy is the first-line standard treatment for HER2-positive advanced gastric cancer.Inetetamab is a novel anti-HER2 drug,and its efficacy and safety in gastric cancer have not yet been reported.AIM To evaluate the efficacy and safety of the S-1 plus oxaliplatin(SOX)regimen combined with inetetamab as a first-line treatment for HER2-positive advanced gastric cancer.METHODS Thirty-eight patients with HER2-positive advanced gastric cancer or gastroeso-phageal junction adenocarcinoma were randomly divided into two groups:One group received inetetamab combined with the SOX regimen,and the other group received trastuzumab combined with the SOX regimen.After 4-6 cycles,patients with stable disease received maintenance therapy.The primary endpoints were progression-free survival(PFS)and overall survival(OS),and the secondary endpoints were the objective response rate,disease control rate,and adverse events(AEs).RESULTS Thirty-seven patients completed the trial,with 18 patients in the inetetamab group and 19 patients in the trastuzumab group.In the inetetamab group,the median PFS was 8.5 months,whereas it was 7.3 months in the trastuzumab group(P=0.046);this difference was significant.The median OS in the inetetamab group vs the trastuzumab group was 15.4 months vs 14.3 months(P=0.33),and the objective response rate was 50%vs 42%(P=0.63),respectively;these differences were not significant.Common AEs included leukopenia,thrombocytopenia,nausea,and vomiting.The incidence rates of grade≥3 AEs were 56%in the inetetamab group and 47%in the trastuzumab group(P=0.63),with no significant difference.CONCLUSION In the first-line treatment of HER2-positive advanced gastric cancer,inetetamab and trastuzumab showed comparable efficacy.The inetetamab group showed superior PFS,and both groups had good safety.

Human epidermal growth factor receptor 2 expression level and combined positive score can evaluate efficacy of advanced gastric cancer

BACKGROUND Although treatment options for gastric cancer(GC)continue to advance,the overall prognosis for patients with GC remains poor.At present,the predictors of treatment efficacy remain controversial except for high microsatellite instability.AIM To develop methods to identify groups of patients with GC who would benefit the most from receiving the combination of a programmed cell death protein 1(PD-1)inhibitor and chemotherapy.METHODS We acquired data from 63 patients with human epidermal growth factor receptor 2(HER2)-negative GC with a histological diagnosis of GC at the Cancer Hospital,Chinese Academy of Medical Sciences between November 2020 and October 2022.All of the patients screened received a PD-1 inhibitor combined with chemotherapy as the first-line treatment.RESULTS As of July 1,2023,the objective response rate was 61.9%,and the disease control rate was 96.8%.The median progression-free survival(mPFS)for all patients was 6.3 months.The median overall survival was not achieved.Survival analysis showed that patients with a combined positive score(CPS)≥1 exhibited an extended trend in progression-free survival(PFS)when compared to patients with a CPS of 0 after receiving a PD-1 inhibitor combined with oxaliplatin and tegafur as the first-line treatment.PFS exhibited a trend for prolongation as the expression level of HER2 increased.Based on PFS,we divided patients into two groups:A treatment group with excellent efficacy and a treatment group with poor efficacy.The mPFS of the excellent efficacy group was 8 months,with a mPFS of 9.1 months after excluding a cohort of patients who received interrupted therapy due to surgery.The mPFS was 4.5 months in patients in the group with poor efficacy who did not receive surgery.Using good/poor efficacy as the endpoint of our study,univariate analysis revealed that both CPS score(P=0.004)and HER2 expression level(P=0.015)were both factors that exerted significant influence on the efficacy of treatment the combination of a PD-1 inhibitor and chemotherapy in patients with advanced GC(AGC).Finally,multivariate analysis confirmed that CPS score was a significant influencing factor.CONCLUSION CPS score and HER2 expression both impacted the efficacy of immunotherapy combined with chemotherapy in AGC patients who were non-positive for HER2.

Therapeutic strategies targeting the epidermal growth factor receptor signaling pathway in metastatic colorectal cancer

More than 1.9 million new colorectal cancer(CRC)cases and 935000 deaths were estimated to occur worldwide in 2020,representing about one in ten cancer cases and deaths.Overall,colorectal ranks third in incidence,but second in mortality.More than half of the patients are in advanced stages at diagnosis.Treatment options are complex because of the heterogeneity of the patient population,including different molecular subtypes.Treatments have included conventional fluorouracil-based chemotherapy,targeted therapy,immunotherapy,etc.In recent years,with the development of genetic testing technology,more and more targeted drugs have been applied to the treatment of CRC,which has further prolonged the survival of metastatic CRC patients.

PRaG 3.0 therapy for human epidermal growth factor receptor 2-positive metastatic pancreatic ductal adenocarcinoma:A case report

BACKGROUND Pancreatic ductal adenocarcinoma(PDAC)is a highly fatal disease with limited effective treatment especially after first-line chemotherapy.The human epidermal growth factor receptor 2(HER-2)immunohistochemistry(IHC)positive is associated with more aggressive clinical behavior and shorter overall survival in PDAC.CASE SUMMARY We present a case of multiple metastatic PDAC with IHC mismatch repair proficient but HER-2 IHC weakly positive at diagnosis that didn’t have tumor regression after first-line nab-paclitaxel plus gemcitabine and PD-1 inhibitor treatment.A novel combination therapy PRaG 3.0 of RC48(HER2-antibody-drug conjugate),radio-therapy,PD-1 inhibitor,granulocyte-macrophage colony-stimulating factor and interleukin-2 was then applied as second-line therapy and the patient had confirmed good partial response with progress-free-survival of 6.5 months and overall survival of 14.2 month.She had not developed any grade 2 or above treatment-related adverse events at any point.Percentage of peripheral CD8^(+) Temra and CD4^(+) Temra were increased during first two activation cycles of PRaG 3.0 treatment containing radiotherapy but deceased to the baseline during the maintenance cycles containing no radiotherapy.CONCLUSION PRaG 3.0 might be a novel strategy for HER2-positive metastatic PDAC patients who failed from previous first-line approach and even PD-1 immunotherapy but needs more data in prospective trials.

Efficacy and safety of dacomitinib as first-line treatment for advanced non-small cell lung cancer patients with epidermal growth factor receptor 21L858R mutation:A multicenter,case-series study in China

Objective:To provide real-world evidence for the application of first-line dacomitinib treatment for epidermal growth factor receptor(EGFR)21L858R mutant non-small cell lung cancer(NSCLC)patients in China and to explore the factors influencing the efficacy and safety.Methods:A longitudinal,consecutive case-series,multicenter study with mixed prospective and retrospective data was conducted.The primary endpoint was progression-free survival(PFS),and the secondary endpoints included duration of treatment(DOT),overall survival(OS),objective response rate(ORR),disease control rate(DCR)and safety.Results:A total of 155 EGFR 21L858R mutant patients treated with first-line dacomitinib were included.The median follow-up time for these patients was 20.4 months.Among 134 patients with evaluable lesions,the ORR was 70.9%and the DCR was 96.3%.The median PFS was 16.3[95%confidence interval(95%CI),13.7−18.9]months.Multivariate Cox regression analysis suggested that the baseline brain metastasis(BM)status[with vs.without BM:hazard ratio(HR),1.331;95%CI,0.720−2.458;P=0.361]and initial doses(45 mg vs.30 mg:HR,0.837;95%CI,0.427−1.641;P=0.604)did not significantly affect the median PFS.The median DOT was 21.0(95%CI,17.5−24.6)months and the median OS was not reached.Genetic tests were performed in 64 patients after progression,among whom 29(45.3%)patients developed the EGFR 20T790M mutation.In addition,among the 46 patients who discontinued dacomitinib treatment after progression,31(67.4%)patients received subsequent third-generation EGFR-tyrosine kinase inhibitors.The most common grade 3−4 adverse events were rash(10.4%),diarrhea(9.1%),stomatitis(7.1%)and paronychia(4.5%).The incidence of grade 3−4 rash was significantly higher in the 45 mg group than that in the 30 mg group(21.9%vs.7.5%,P=0.042).Conclusions:First-line dacomitinib treatment demonstrated promising efficacy and tolerable adverse events among EGFR 21L858R mutant NSCLC patients in China.

Advances in targeted therapy for human epidermal growth factor receptor 2 positive in advanced gastric cancer

Emerging therapeutic methods represented by targeted therapy are effective supplements to traditional first-line chemoradiotherapy resistance.Human epidermal growth factor receptor 2(HER2)is one of the most important targets in targeted therapy for gastric cancer.Trastuzumab combined with chemotherapy has been used as the first-line treatment for advanced gastric cancer.The safety and efficacy of pertuzumab and margetuximab in the treatment of gastric cancer have been verified.However,monoclonal antibodies,due to their large molecular weight,inability to penetrate the blood-brain barrier,and drug resistance,lead to decreased therapeutic efficacy,so it is necessary to explore the efficacy of other HER2-targeting therapies in gastric cancer.Small-molecule tyrosine kinase inhibitors,such as lapatinib and pyrrotinib,have the advantages of small molecular weight,penetrating the blood-brain barrier and high oral bioavailability,and are expected to become the drugs of choice for perioperative treatment and neoadjuvant therapy of gastric cancer after validation by large-scale clinical trials in the future.Antibo-drug conjugate,such as T-DM1 and T-DXd,can overcome the resistance of monoclonal antibodies despite their different mechanisms of tumor killing,and are a supplement for the treatment of patients who have failed the treatment of monoclonal antibodies such as trastuzumab.Therefore,after more detailed stratification of gastric cancer patients,various gastric cancer drugs targeting HER2 are expected to play a more significant role.

Concomitant epidermal growth factor receptor mutation/c-ros oncogene 1 rearrangement in non-small cell lung cancer: A case report

BACKGROUND Epidermal growth factor receptor(EGFR)mutation and c-ros oncogene 1(ROS1)rearrangement are key genetic alterations and predictive tumor markers for non-small cell lung cancer(NSCLC)and are typically considered to be mutually exc-lusive.EGFR/ROS1 co-mutation is a rare event,and the standard treatment appr-oach for such cases is still equivocal.CASE SUMMARY Herein,we report the case of a 64-year-old woman diagnosed with lung adenocar-cinoma,with concomitant EGFR L858R mutation and ROS1 rearrangement.The patient received two cycles of chemotherapy after surgery,but the disease prog-ressed.Following 1-month treatment with gefitinib,the disease progressed again.However,after switching to crizotinib,the lesion became stable.Currently,crizotinib has been administered for over 53 months with a remarkable treatment effect.CONCLUSION The efficacy of EGFR tyrosine kinase inhibitors and crizotinib was vastly different in this NSCLC patient with EGFR/ROS1 co-mutation.This report will aid future treatment of such patients.

Signaling pathways involved in the inhibition of epidermal growth factor receptor by erlotinib in hepatocellular cancer

AIM： To examine the underlying mechanisms of erlotinib-induced growth inhibition in hepatocellular carcinoma （HCC）. METHODS： Erlotinib-induced alterations in gene expression were evaluated using cDNA array technology; changes in protein expression and/or protein activation due to erlotinib treatment as well as IGF-1-induced EGFR transactivation were investigated using Western blotting. RESULTS： Erlotinib treatment inhibited the mitogen activated protein （MAP）-kinase pathway and signal transducer of activation and transcription （STAT）- mediated signaling which led to an altered expression of apoptosis and cell cycle regulating genes as demonstrated by cDNA array technology. Overexpression of proapoptotic factors like caspases and gadds associated with a down-regulation of antiapoptotic factors like Bcl-2, Bcl-XL or jun D accounted for erlotinib＇s potency to induce apoptosis. Downregulation of cell cycle regulators promoting the G1/S-transition and overexpression of cyclin-dependent kinase inhibitors and gadds contributed to the induction of a G1/G0-arrest in response to erlotinib. Furthermore, we displayed the transactivation of EGFR-mediated signaling by the IGF-1-receptor and showed erlotinib＇s inhibitory effects on the receptor-receptor cross talk. CONCLUSION： Our study sheds light on the understanding of the mechanisms of action of EGFR-TK- inhibition in HCC-cells and thus might facilitate the design of combination therapies that act additively or synergistically. Moreover, our data on the pathways responding to erlotinib treatment could be helpful in predicting the responsiveness of tumors to EGFR-TKIs in the future.

Biomarkers of skin toxicity induced by anti-epidermal growthfactor receptor antibody treatment in colorectal cancer

Skin toxicity is a common symptom of anti-epidermal rowth factor receptor(EGFR) antibody treatment and is also a predictive marker of its efficacy in colorectal cancer patients. However, severe skin disorders induced by such antibodies negatively impact on the quality of life of patients and decreases drug compliance during treatment. If we can predict the high-risk group susceptible to severe skin toxicity before treatment, we can undertake the early management of any arising skin disorders and formulate a more accurate prognosis for anti-EGFR antibody treatment. Previous studies have identified molecular markers of skin toxicity induced by anti-EGFR antibody, such as EGFR polymorphisms, the expression of inflammatory chemokines and serum levels of EGFR ligands. A clinical trial was undertaken involving the escalation of cetuximab doses, guided by the grade of skin toxicity observed, such as no or low-grade, in metastatic colorectal cancer(the EVEREST study). The dose escalation of cetuximab was confirmed by a safety profile and had the tendency to achieve a higher response rate in KRAS wild-type patients. A large, prospective randomized trial is now ongoing(EVEREST 2) and the results of this trial may contribute to personalized medicine in KRAS wild-type colorectal cancer patients.

Repurposed anti-cancer epidermal growth factor receptor inhibitors: mechanisms of neuroprotective effects in Alzheimer’s disease

Numerous molecular mechanisms are being examined in an attempt to discover disease-modifying drugs to slow down the underlying neurodegeneration in Alzheimer’s disease.Recent studies have shown the beneficial effects of epidermal growth factor receptor inhibitors on the enhancement of behavioral and pathological sequelae in Alzheimer’s disease.Despite the promising effects of epidermal growth factor receptor inhibitors in Alzheimer’s disease,there is no irrefutable neuroprotective evidence in well-established animal models using epidermal growth factor receptor inhibitors due to many un-explored downstream signaling pathways.This caused controversy about the potential involvement of epidermal growth factor receptor inhibitors in any prospective clinical trial.In this review,the mystery beyond the under-investigation of epidermal growth factor receptor in Alzheimer’s disease will be discussed.Furthermore,their molecular mechanisms in neurodegeneration will be explained.Also,we will shed light on SARS-COVID-19 induced neurological manifestations mediated by epidermal growth factor modulation.Finally,we will discuss future perspectives and under-examined epidermal growth factor receptor downstream signaling pathways that warrant more exploration.We conclude that epidermal growth factor receptor inhibitors are novel effective therapeutic approaches that require further research in attempts to be repositioned in the delay of Alzheimer’s disease progression.

Role of human epidermal growth factor receptor 2 in gastric cancer:Biological and pharmacological aspects

Amplification of the human epidermal growth factor receptor 2 (HER2) gene and overexpression of the HER2 protein is found in 15%-20% of patients with gastric and gastroesophageal junction cancer. The degree of HER2 overexpression and amplification varies with the location of the carcinoma, with higher expression in the gastroesophageal and proximal parts compared to the distal parts of the stomach. Further, HER2 overexpression and amplification also seems to be related to the Lauren histological classification, with higher levels found in the intestinal phenotype compared to the diffuse and mixed types. The prognostic properties of HER2 overexpression and amplification are still under debate, but a large number of studies seem to indicate that HER2 is a negative prognostic factor. The usefulness of HER2 targeted therapy in gastric cancer was demonstrated in the ToGA trial, where HER2-positive patients with advanced gastric and gastroesophageal junction adenocarcinoma were randomized to receive 5-FU/capecitabine and cisplatin, either alone or in combination with trastuzumab. A statically significant gain in overall survival was seen in patients who received the combined treatment of trastuzumab and chemotherapy. Patients with a strong overexpression of the HER2 protein (IHC3+) specifically benefited from the treatment, with a median overall survival of 17.9 mo. As a consequence of the positive results of the ToGA trial, patients with advanced gastric or gastroesophageal junction adenocarcinoma are now routinely tested for HER2. The ToGA trial must be characterized as a landmark in the treatment of gastric cancer and it has paved the way for a number of new HER2 targeted compounds such as pertuzumab, ado-trastuzumab emtansine, lapatinib, afatinib, and dacomitinib, which are currently undergoing phase II and III clinical testing. Overall, this review will discuss the current status of HER2 in gastric and gastroesophageal junction cancer and the future direction in relation to HER2 target therapy.

Mechanisms of resistance to anti-epidermal growth factor receptor inhibitors in metastatic colorectal cancer

The prognosis of patients with metastatic colorectal cancer (mCRC) remain poor despite the impressive improvement of treatments observed over the last 20 years that led to an increase in median overall survival from 6 mo, with the only best supportive care, to approximately 30 mo with the introduction of active chemotherapy drugs and targeted agents. The monoclonal antibodies (moAbs) cetuximab and panitumumab, directed against the epidermal growth factor receptor (EGFR), undoubtedly represent a major step forward in the treatment of mCRC, given the relevant efficacy in terms of progression-free survival, overall survival, response rate, and quality of life observed in several phase III clinical trials among different lines of treatment. However, the anti-EGFR moAbs were shown only to be effective in a subset of patients. For instance, KRAS and NRAS mutations have been identified as biomarkers of resistance to these drugs, improving the selection of patients who might derive a benefit from these treatments. Nevertheless, several other alterations might affect the response to these drugs, and unfortunately, even the responders eventually become resistant by developing secondary (or acquired) resistance in approximately 13-18 mo. Several studies highlighted that the landscape of responsible alterations of both primary and acquired resistance to anti-EGFR drugs biochemically converge into MEK-ERK and PIK3CA-AKT pathways. In this review, we describe the currently known mechanisms of primary and acquired resistance to anti-EGFR moAbs together with the various strategies evaluated to prevent, overcame or revert them.

Epidermal growth factor receptor tyrosine kinase inhibitors for non-small cell lung cancer

First-generation epidermal growth factor receptor tyrosine kinase inhibitors(EGFR-TKIs), including gefitinib and erlotinib, have proven to be highly effective agents for advanced non-small cell lung cancer(NSCLC) in patients harboring an activating EGFR mutation such as the exon 19 deletion mutation and L858 R. Although those reversible small molecular targeted agents provide a significant response and survival benefit, all responders eventually acquire resistance. Secondgeneration EGFR-targeting agents, such as irreversible EGFR/HER2 tyrosine kinase inhibitors and pan-HER TKIs, may improve survival further and be useful for patients who acquired resistance to first-generation EGFR-TKIs. This review discusses novel therapeutic strategies for EGFR-mutated advanced NSCLC using first- and second-generation EGFR-TKIs.

Effects of epidermal growth factor receptor inhibitor on proliferative cholangitis in hepatolithiasis

BACKGROUND： There is currently no effective medication to prevent stone recurrence after choledochoscopic lithotomy or to treat proliferative cholangitis（PC）, which is the pathologic basis of hepatolithiasis. This study aimed to investigate whether gefitinib, an epidermal growth factor receptor（EGFR） inhibitor, inhibited cholangio hyperplasia and lithogenesis in PC.METHODS： After cholangioscopic lithotomy, indwelling catheters were placed in the diseased bile duct lumens in 94 patients with hepatolithiasis. Subsequently, 49 of the 94 patients were treated with 250 mg gefitinib solution via a catheter twice a week, and they were subjected to choledochoscopic biopsy at 6 and 12 weeks. The rest 45 hepatolithiasis patients without gefitinib treatment served as controls.RESULTS： The expressions of EGFR, PCNA and procollagen I were significantly reduced in the patients treated with gefitinib in 12 weeks compared with those in the control group. Patients in the gefitinib group had a much lower degree of hyperplasia of the biliary epithelium, submucosal glands and collagen fibers compared with those in the control group. Gefitinib treatment significantly decreased mucin 3 expression and β-glucuronidase activity.CONCLUSION： Postoperative gefitinib treatment could significantly inhibit PC-mediated hyperplasia and lithogenesis, which might provide a novel strategy for the prevention of biliary restenosis and stone recurrence in patients with hepatolithiasis.

Inhibition of invasiveness and expression of epidermal growth factor receptor in human colorectal carcinoma cells induced by retinoic acid

Human amniotic basement membrane (HABM) model and agarose drop explant method were used to in-vestigate the effects of retinoic acid(RA) on the invasive-ness alld adhesiveness to the basement membrane, and the migration of a highly invassive human colorectal cancer cell line CCL229. Results showed that 5 ×106 MRA markedly reduced the in vitro invasiveness and adhesiveness to the HABM, and the migration of the CCL229 cells. In addi-tion, to elucidate the relation between expression of epider-mal growth factor receptor (EGFR) and the invasiveness of the colorectal carcinoma cells, two well-differentiated, but with different invasiveness colorectal cancer cell lines were compared at mRNA level for expressioll of EGFR by using EGFR cDNA probe labeled with digoxigenin (DIG). Expression of EGFR was showll to be markedly higher in the highly invassive CCL229 cells than that in the low in- vasive CX-1 cells. Furthermore, expression of EGFR in RA treated CCL229 cells gradually decreased with time,the level being the lowest on day 6 of the RA treatment.

Therapeutic Effect of First-line Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor (EGFR-TKI)Combined with Whole Brain Radiotherapy on Patients with EGFR Mutation-positive Lung Adenocarcinoma and Brain Metastases

This study compared the therapeutic effect of first-line epidermal growth factor receptor tyrosine kinase inhibitor(EGFR-TKI)with that of EGFR-TKI plus whole brain radiotherapy(WBRT)on patients with EGFR mutation-positive lung adenocarcinoma and brain metastases.A total of 139 patients with lung adenocarcinoma and brain metastases treated with first-line EGFR-TK1therapy from September 2008 to December 2017 were enrolled in this study.The study endpoints were intracranial time to progression(TTP)and overall survival(OS).The effects of clinical pathological parameters and EGFR gene status on the study endpoints were compared.The results showed that the intracranial TTP was significantly longer in EGFR-TKI plus WBRT group than in EGFR-TKI group (median 30.0 vs.18.2 months,χ2=10.824,P=0.001),but no significant difference in the OS was noted between the two groups (median 48.0 vs.41.1 months,χ2=0.012, P=0.912).Also,there was no statistically significant difference in the OS between patients treated with early and late radiotherapy (P=0.849)and between those with asymptomatic and those with symptomatic intracranial metastases (P=0.189).The OS and intracranial TTP of patients with intracranial oligometastases (≤3metastatic sites)were not significantly different from those of patients with multiple intracranial metastases (P=0.104 and P=0.357,respectively),and exon 19 and exon 21 mutations didn't show significant effects on the OS and intracranial TTP of patients (P=0.418 and P=0.386,respectively).In conclusion,there was no statistically significant difference in the OS between the EGFR-TKI alone group and EGFR-TK1 plus WBRT group.However, simultaneous use of WBRT was found to significantly prolong intracranial TTP and improve cerebral symptoms,and thus EGFR-TKI and WBRT combined may be clinically beneficial for patients with EGFR mutation-positive lung adenocarcinoma and brain metastases.

JAK3 inhibitor Ⅵ is a mutant specific inhibitor for epidermal growth factor receptor with the gatekeeper mutation T790M

AIM:To identify non-quinazoline kinase inhibitors effective against drug resistant mutants of epidermal growth factor receptor(EGFR).METHODS:A kinase inhibitor library was subjected to screening for specific inhibition pertaining to the in vitro kinase activation of EGFR with the gatekeeper mutation T790 M,which is resistant to small molecular weight tyrosine kinase inhibitors(TKIs) for EGFR in nonsmall cell lung cancers(NSCLCs). This inhibitory effect was confirmed by measuring autophosphorylation of EGFR T790M/L858 R in NCI-H1975 cells,an NSCLC cell line harboring the gatekeeper mutation. The effects of a candidate compound,Janus kinase 3(JAK3) inhibitor Ⅵ,on cell proliferation were evaluated using the MTT assay and were compared between T790M-positive and-negative lung cancer cell lines. JAK3 inhibitor Ⅵ was modeled into the ATP-binding pocket of EGFR T790M/L858 R. Potential physical interactions between the compound and kinase domains of wild-type(WT) or mutant EGFRs or JAK3 were estimated by calculating binding energy. The gatekeeper residues of EGFRs and JAKs were aligned to discuss the similarities among EGFR T790 M and JAKs. RESULTS:We found that JAK3 inhibitor Ⅵ,a known inhibitor for JAK3 tyrosine kinase,selectively inhibits EGFR T790M/L858 R,but has weaker inhibitory effects on the WT EGFR in vitro. JAK3 inhibitor Ⅵ also specifically reduced autophosphorylation of EGFR T790M/L858 R in NCI-H1975 cells upon EGF stimulation,but did not show the inhibitory effect on WT EGFR in A431 cells. Furthermore,JAK3 inhibitor Ⅵ suppressed the proliferationof NCI-H1975 cells,but showed limited inhibitory effects on the WT EGFR-expressing cell lines A431 and A549.A docking simulation between JAK3 inhibitor Ⅵ and the ATP-binding pocket of EGFR T790M/L858 R predicted a potential binding status with hydrogen bonds. Estimated binding energy of JAK3 inhibitor Ⅵ to EGFR T790M/L858 R was more stable than its binding energy to the WT EGFR. Amino acid sequence alignments revealed that the gatekeeper residues of JAK family kinases are methionine in WT,similar to EGFR T790 M,suggesting that TKIs for JAKs may also be effective for EGFR T790 M. CONCLUSION:Our findings demonstrate that JAK3 inhibitor Ⅵ is a gatekeeper mutant selective TKI and offer a strategy to search for new EGFR T790 M inhibitors.

Review of epidermal growth factor receptor-tyrosine kinase inhibitors administration to non-small-cell lung cancer patients undergoing hemodialysis

Non-small-cell lung cancer(NSCLC)causes significant mortality worldwide.Patients with chronic renal failure have an increased risk of developing lungcancer.NSCLC Patients with chronic renal failure undergoing hemodialysis(HD)often exhibit poor performance,and chemotherapy is generally contraindicated.Oral epidermal growth factor receptor(EGFR)-tyrosine kinase inhibitors(TKIs)are effective treatment agents for NSCLC patients.However,the benefits andadverse effects of EGFR-TKIs in NSCLC undergoing HD are known.There are noclinical studies on the effects of EGFR-TKIs on NSCLC patients undergoing HD.We reviewed all previous case reports about EGFR-TKIs in NSCLC patientsundergoing HD.It is difficult to design studies about the effects of EGFR-TKIs inpatients undergoing HD,and this review is quite important.EGFR-TKIs are welltolerated in patients undergoing HD.The main routes of elimination of EGFRTKIsare metabolism via the liver,and renal elimination is minor.Therecommended doses and pharmacokinetics of these EGFR-TKIs for patientsundergoing HD are similar to those for patients with normal renal function.Theplasma protein binding of EGFR-TKIs is very high,and it is not necessary toadjust the dose after HD.In conclusion,EGFR-TKIs are effective and welltolerated in patients undergoing HD.

Inhibition of epidermal growth factor receptor signaling protects human malignant glioma cells from hypoxia - induced cell death

Epidermal growth factor receptor(EGFR)signaling has become an importanttarget for drug development becauseEGFR signaling enhances tumor cell proliferation,migration,and invasion and inhibits apoptosis.However,theresults of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing.Here,wereport a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hy-poxia,which contrasts with their proapoptotic effects under normoxia.Under hypoxic conditions,both agents re-

Is there a role for epidermal growth factor receptor tyrosine kinase inhibitors in epidermal growth factor receptor wildtype non-small cell lung cancer?

Non-small cell lung cancer(NSCLC) is the most common type of lung cancer with a world-wide annual incidence of around 1.3 million. The majority of patients arediagnosed with advanced disease and survival remains poor. However, relevant advances have occurred in recent years through the identification of biomarkers that predict for benefit of therapeutic agents. This is exemplified by the efficacy of epidermal growth factor receptor(EGFR) tyrosine kinase inhibitors for the treatment of EGFR mutant patients. These drugs have also shown efficacy in unselected populations but this point remains controversial. Here we have reviewed the clinical data that demonstrate a small but consistent subgroup of EGFR wild-type patients with NSCLC that obtain a clinical benefit from these drugs. Moreover, we review the biological rationale that may explain this benefit observed in the clinical setting.