ERβ1 Expression Patterns Have Different Effects On EGFR TKIs Treatment Response in EGFR Mutant Lung Adenocarcinomas.

Abstract Background: Estrogen receptor β (ERβ) can regulate cellular signaling through non-genomic mechanisms, potentially promoting resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanisms underlying the ERβ-mediated resistance to EGFR TKIs remain poorly understood. Methods: qRT-PCR was performed to investigate ERβ1 and ERβ5 expression levels in cell lines. The localization of ERβ and ERβ1 within cells was assessed using immunocytochemistry and immunofluorescence. The effect of estradiol and/or gefitinib on EGFR signaling pathways was determined by western blot. Cell viability and colony formation assays were used to assess gefitinib response for different cell lines. The apoptosis was verified by tunel and western blot. Immunohistochemistry was used to assess the expression of ERβ1 in lung adenocarcinoma tissues. Patient survival was estimated using the Kaplan-Meier method, and comparisons between groups were conducted using log-rank tests. Results: PC9 cell lines stably overexpressing ERβ1 or ERβ1/ERβ5 were established successfully. Immunofluorescence revealed that ERβ5 overexpression partly retained ERβ1 in the cytoplasm. Immunoblotting analyses revealed that EGFR pathway activation levels were higher in PC9/ERβ1/5 cells than those in PC9/ERβ1 or control PC9 cells. In the presence of estradiol, PI3K/AKT/mTOR pathway activation levels were higher in ERβ1/5-expressing cells than those in ERβ1-expressing cells. Additionally, PC9/ERβ1/5 cells were less prone to the cytotoxic and pro-apoptotic effects of gefitinib compared with PC9/ERβ1 or control PC9 cells. Conclusion: Cytoplasmic ERβ1 was associated with poor progression-free survival in lung cancer patients treated with EGFR TKIs. These results suggest that anti-estrogen therapy might reverse EGFR TKI treatment resistance to some extent in selected patients.

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Prognostic Value of BIM Deletion in EGFR-Mutant NSCLC Patients Treated with EGFR-TKIs: A Meta-Analysis

BioMed Research International ◽

10.1155/2021/3621828 ◽

2021 ◽

Vol 2021 ◽

pp. 1-13

Author(s):

Fangfang Lv ◽

Liang Sun ◽

Qiuping Yang ◽

Zheng Pan ◽

Yuhua Zhang

Keyword(s):

Kinase Inhibitors ◽

Meta Analysis ◽

Objective Response ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Deletion Polymorphism ◽

Asian Populations ◽

Egfr Mutant ◽

Nsclc Patients ◽

Egfr Tkis

Background. Resistance to epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) is inevitable in EGFR-mutant non-small-cell lung cancer (NSCLC) patients. A germline 2903 bp deletion polymorphism of Bcl-2-like protein 11 (BIM) causes reduced expression of proapoptotic BH3-only BIM protein and blocks TKI-induced apoptosis of tumor cells. Yet the association between the deletion polymorphism and response to EGFR-TKI treatment remains inconsistent among clinical observations. Thus, we performed the present meta-analysis. Methods. Eligible studies were identified by searching PubMed, Embase, and ClinicalTrials.gov databases prior to March 31, 2021. Hazard ratios (HRs) and 95% confidence intervals (CIs) of progression-free survival (PFS) and overall survival (OS) and odds ratios (ORs) and 95% CIs of objective response rate (ORR) and disease control rate (DCR) were calculated by using a random effects model. Sensitivity, metaregression, and publication bias analyses were also performed. Results. A total of 20 datasets (3003 EGFR-mutant NSCLC patients receiving EGFR-TKIs from 18 studies) were included. There were 475 (15.8%) patients having the 2903-bp intron deletion of BIM and 2528 (84.2%) wild-type patients. BIM deletion predicted significantly shorter PFS ( HR = 1.35 , 95% CI: 1.10-1.64, P = 0.003 ) and a tendency toward an unfavorable OS ( HR = 1.22 , 95% CI: 0.99-1.50, P = 0.068 ). Patients with deletion polymorphism had lower ORR ( OR = 0.60 , 95% CI: 0.42-0.85, P = 0.004 ) and DCR ( OR = 0.59 , 95% CI: 0.38-0.90, P = 0.014 ) compared with those without deletion. Conclusion. BIM deletion polymorphism may confer resistance to EGFR-TKIs and can be used as a biomarker to predict treatment response to EGFR-TKIs in EGFR-mutant NSCLC patients from Asian populations.

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Understanding real-world outcomes in patients with NSCLC who progress on 1st-/2nd-generation EGFR TKIs.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.e20589 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. e20589-e20589

Author(s):

Ancilla Fernandes ◽

Karen E Skinner ◽

Mark Stephen Walker ◽

Melissa Pavilack ◽

Ari M. Vanderwalde

Keyword(s):

Treatment Period ◽

Real World ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Retrospective Chart Review ◽

Progression Free Survival ◽

2Nd Generation ◽

Egfr Tyrosine Kinase Inhibitors ◽

Tki Treatment ◽

Egfr Tkis

e20589 Background: Epidermal growth factor receptor (EGFR)tyrosine kinase inhibitors (TKIs) are recommended for patients (pts) with EGFR mutation ( EGFRm) positive non-small cell lung cancer (NSCLC). Limited data are available for real-world outcomes in pts who experience progression on 1st-/2nd-generation EGFR TKIs, which was the focus of this study. Methods: A retrospective chart review of pts with advanced NSCLC (stage IIIb/IV) from 10 US community oncology practices was conducted. Patients were included if they were diagnosed 1/1/2008—1/1/2015, were treated with erlotinib or afatinib (TKIs) either first line (1L) or second line (2L), and had disease progression (per clinician’s assessment) prior to 10/31/2015. Pts were classified into cohorts based on TKI initiation (1L or 2L) and EGFRm status. Progression-free survival (PFS) and overall survival (OS) were evaluated for the TKI treatment period and the post-progression period. Results: The study included 364 pts: 77.7% white, 17.3% African American; mean (SD) age 66.3 (11.3) years. PFS and OS were longer for 1L and EGFRm+ pt cohorts during the TKI treatment period. After progression, 25.3% (80/316) pts continued TKI, while around half received chemotherapy (56.3%; 178/316). The effects of other variables evaluated as predictors of PFS and OS were largely nonsignificant. Conclusions: Outcomes were worse after progression irrespective of EGFRm status and whether TKI was initiated 1L or 2L. This finding highlights the need for therapeutic options that improve outcomes in pts after progression on a 1st-/2nd-generation EGFR TKI. [Table: see text]

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Lung Adenocarcinoma Patient Harboring EGFR-KDD Achieve Durable Response to Afatinib: A Case Report and Literature Review

Frontiers in Oncology ◽

10.3389/fonc.2021.605853 ◽

2021 ◽

Vol 11 ◽

Author(s):

Lingling Zhao ◽

Zhen Wang ◽

Haiwei Du ◽

Songan Chen ◽

Pingli Wang

Keyword(s):

Lung Adenocarcinoma ◽

Kinase Inhibitors ◽

Case Reports ◽

Rapid Development ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Kinase Domain ◽

Durable Response ◽

Egfr Tyrosine Kinase Inhibitors ◽

Egfr Tkis

The rapid development of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) has revolutionized the treatment of patients with advanced or metastatic non-small cell lung cancer (NSCLC) harboring EGFR mutations including but not limited to exon 19 deletions (19 del) and point mutation L858R in exon 21. However, the efficacy of EGFR-TKIs in patients with rare mutations, such as EGFR-kinase domain duplication (KDD), remains elusive. EGFR-KDD often results from in-frame tandem duplication of EGFR exons 18–25, causing subsequent constitutive activation of EGFR signaling. Several case reports have revealed the efficacies of EGFR-TKIs in advanced lung adenocarcinoma (LUAD) with EGFR-KDD but yielded variable antitumor responses. In the present study, we report a 61-year-old male patient diagnosed with T1N3M0 (stage IIIB) LUAD harboring EGFR-KDD involving exons 18–25. He was treated with afatinib and achieved partial response (PR) with progression-free survival (PFS) of 12 months and counting. Our work, confirming EGFR-KDD as an oncogenic driver and therapeutic target, provides clinical evidence to administer EGFR-TKIs in patients with advanced LUAD harboring EGFR-KDD.

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Consistency between K-ras mutation in peripheral blood and matched tumor tissues detected by PCR-RFLP in Chinese patients with advanced NSCLC and its clinical significance analysis

Journal of Clinical Oncology ◽

10.1200/jco.2009.27.15_suppl.8090 ◽

2009 ◽

Vol 27 (15_suppl) ◽

pp. 8090-8090

Author(s):

W. Shuhang ◽

H. Bai ◽

J. Zhao ◽

C. J. Duan ◽

L. Yang ◽

...

Keyword(s):

Peripheral Blood ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Chinese Patients ◽

Plasma Dna ◽

Ras Mutation ◽

Tumor Tissues ◽

Pcr Rflp ◽

Egfr Tkis

8090 Background: To explore the consistency between K-ras mutation in peripheral blood and matched tumor tissues detected by PCR-RFLP and analyze the prognostic effects of K-ras mutation in peripheral blood in Chinese NSCLC patients (pts) treated by epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs). Methods: Plasma free DNA and matched tumor samples were collected from 264 hospitalized pts in Department of Thoracic Oncology, Peking University School of Oncology between Jan 2005 and Feb 2008. K-ras mutations were detected in coden 12 and 13 of exon 1 by PCR-RFLP and then verificated by sequencing. We compared the mutations in plasma samples and matched tumor tissues which determined an association between K-ras mutation status and clinical outcomes. Results: In 264 pts, K-ras mutation rates in codon 12 and 13 of exons 1 in peripheral blood were 11.36% (30/264) and 0.75% (2/264), also 9.84% (26/264) and 1.13% (3/264) in matched tumor tissues, respectively. Consistency of mutation in codon 12 between in tissues and plasma was 94%(248/264) (Kappa=0.686,P<0.001). Among 107 pts who received EGFR-TKIs treatment, the effective rate(RR), progression-free survival (PFS) and median survival time (MST) in pts with K-ras mutation in plasma DNA were 6.7.%, 2.7 months and 20.5 months, respectively, all which were lower than those of pts with wild type K-ras (32.5%, 23.7 months, 31.5 months; P=0.001, P=0.001, P=0.278, respectively). Conclusions: There is a high consistency of K-ras mutation rate between plasma DNA and matched tumor tissues. K-ras mutation in plasma is able to predict both response and PFS of NSCLC pts with EGFR-TKIs treatment. No significant financial relationships to disclose.

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Synthesis and Biological Evaluation of Some Novel Thiophene-bearing Quinazoline Derivatives as EGFR Inhibitors

Letters in Drug Design & Discovery ◽

10.2174/1570180815666180803125935 ◽

2018 ◽

Vol 16 (2) ◽

pp. 102-110 ◽

Cited By ~ 1

Author(s):

Min Zou ◽

Bo Jin ◽

Yanrong Liu ◽

Huiping Chen ◽

Zhuangli Zhang ◽

...

Keyword(s):

Western Blot ◽

Cell Lines ◽

Kinase Inhibitors ◽

Bromine Atom ◽

A549 Cells ◽

Growth Factor Receptor ◽

Biological Evaluation ◽

Egfr Inhibitors ◽

A431 Cells ◽

Quinazoline Derivatives

Background:With the approval of gefitinib, erlotinib, afatinib, and osimertinib for clinical use, targeting Epidermal Growth Factor Receptor (EGFR) has been intensively pursued. Similar to most therapies, challenges related to the treatment resistance against these drugs have emerged over time, so new EGFR Tyrosine Kinase Inhibitors (TKIs) need to be developed. This study aimed to investigate the potential use of a series of thiophene-bearing quinazoline derivatives as EGFR inhibitors. We designed and synthesized nine quinazolin derivatives, among which five compounds (5e, 5f, 5g, 5h, and 5i) were reported for the first time. </P><P> Methods: Two cancer cell lines, A431 (overexpressing EGFR) and A549 (EGFR wild-type and Kras mutation), were treated by these compounds and subjected to MTT assay. The A431 cells were selected for further treatment (5e) and Western blot analysis.Results:Although the compounds exerted no obvious effects on the proliferation of A549 cells, seven out of the nine compounds significantly inhibited the growth of A431 cells. In particular, the IC50 values of 5e and erlotinib were nearly equal. Western blot results showed that 5e significantly inhibited EGFR autophosphorylation in A431 cells. Structure-activity relationships indicated that quinazolines bearing 6,7-side chains were more potent than those unsubstituted at the 6,7-positions. Moreover, electron-withdrawing hydrophobic groups on the 5-position of the thiophene were preferred, such as chlorine or bromine atom.Conclusion:Nine 4-aminoquinazolin derivatives were designed, synthesized, and evaluated against A431 and A549 cell lines. Seven compounds significantly inhibited the growth of A431 cells. In particular, 5e possessed similar antitumor potency to that of erlotinib.

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Genetic and treatment profiles of patients with concurrent Epidermal Growth Factor Receptor (EGFR) and Anaplastic Lymphoma Kinase (ALK) mutations

BMC Cancer ◽

10.1186/s12885-021-08824-2 ◽

2021 ◽

Vol 21 (1) ◽

Author(s):

Xiaodan Yang ◽

Jia Zhong ◽

Zhuo Yu ◽

Minglei Zhuo ◽

Min Zhang ◽

...

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Egfr Mutations ◽

Resistance Mutations ◽

Lung Cancer Patients ◽

Anaplastic Lymphoma ◽

Egfr Tkis

Abstract Background EGFR and ALK alternations often contribute to human malignancies, including lung cancer. EGFR and ALK mutations are usually sensitive to EGFR-tyrosine kinase inhibitors (TKIs) and ALK-TKIs. Although generally mutually exclusive, these mutations do co-exist in rare cases. This study investigated the frequencies, clinical characteristics, therapeutic efficacies, and genetic profiles of lung cancer patients with EGFR and ALK co-mutations. Methods Patients with concurrent EGFR and ALK mutations were included in this study, which analyzed mutation profiles and treatment histories. SPSS20.0 were used for survival analysis. Results Among 271 ALK-positive (ALK-pos) and 2975 EGFR-positive (EGFR-pos) patients in our database, nine (2.6% of ALK-pos and 0.2% of EGFR-pos) patients had concurrent EGFR and ALK mutations (including three exon19 Indel + EML4-ALK, two exon19 Indel + STRN-ALK, two L858R + L1152R, one L858R + EML4-ALK, and one G719C + S768I + STRN-ALK). Eight patients had at least one type of EGFR-TKIs treatment. The median progression free survival (PFS) of these patients on first-generation EGFR-TKIs was 14.5 months (95% CI: 11 - NR). Of these eight patients, one who progressed on Gefitinib and subsequently on Osimertinib had a T790M + C797G. The other seven EGFR-TKIs resistance patients had no known resistance mutations. No patients had ALK mutations before treatment, so ALK mutations may have developed as resistance mechanisms during EGFR-TKIs therapies. EGFR-TKIs-treated patients with EGFR/ALK L1152R mutations generally had a shorter PFS than patients with other mutation combinations. Conclusions ALK and EGFR mutations coincide at a relatively low frequency in lung cancer patients. ALK mutations developed either synchronously or heterochronously with EGFR mutations. Two ALK mutations (L1152R and STRN-ALK) may co-exist with EGFR mutations at a higher frequency than others. Most EGFR/ALK co-alteration patients (other than the EGFR/ALK L1152R type) can benefit from first line EGFR-TKIs.

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EGFR-Mutated Squamous Cell Lung Cancer and Its Association With Outcomes

Frontiers in Oncology ◽

10.3389/fonc.2021.680804 ◽

2021 ◽

Vol 11 ◽

Author(s):

Rui Jin ◽

Ling Peng ◽

Jiawei Shou ◽

Jin Wang ◽

Yin Jin ◽

...

Keyword(s):

Lung Adenocarcinoma ◽

Squamous Cell ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Lung Squamous Cell Carcinoma ◽

Stage Iv ◽

Progression Free Survival ◽

Wild Type ◽

Egfr Tki ◽

Egfr Tkis

BackgroundThe therapeutic efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in advanced EGFR-mutant lung squamous cell carcinoma (SCC) patients remains uncertain. Furthermore, the factors underlying the responsiveness have not been fully investigated. We therefore investigated the link between genomic profiles and EGFR-TKI efficacy.Material and MethodsWe consecutively enrolled stage IV, EGFR-mutant, and EGFR-TKI–treated patients with SCC. Patients with EGFR wild-type lung SCC and EGFR-mutant lung adenocarcinoma were consecutively enrolled as controls, and next-generation sequencing (NGS) was performed.ResultsIn total, 28 EGFR-mutant lung SCC, 41 EGFR-mutant lung adenocarcinoma, and 40 EGFR wild-type lung SCC patients were included. Among the patients with EGFR mutations, shorter progression-free survival (PFS) was observed in SCC compared to adenocarcinoma (4.6 vs. 11.0 months, P<0.001). Comparison of the genomic profiles revealed that EGFR-mutant SCC patients had similar mutation characteristics to EGFR-mutant adenocarcinoma patients, but differed from those with EGFR wild-type SCC. Further exploration of EGFR-mutant SCC revealed that mutations in CREBBP (P = 0.005), ZNF217 (P = 0.016), and the Wnt (P = 0.027) pathway were negatively associated with PFS. Mutations in GRM8 (P = 0.025) were associated with improved PFS.ConclusionsEGFR-mutant lung SCC has a worse prognosis than EGFR-mutant adenocarcinoma. Mutations in other genes, such as CREBBP, ZNF217, GRM8, or Wnt that had implications on PFS raise the possibility of understanding mechanisms of resistance to EGFR-TKI in lung SCC, which will aid identification of potential beneficial subgroups of patients with EGFR-mutant SCCs receiving EGFR-TKIs.

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Efficacy of Osimertinib in NSCLC Harboring Uncommon EGFR L861Q and Concurrent Mutations: Case Report and Literature Review

Frontiers in Oncology ◽

10.3389/fonc.2021.731572 ◽

2021 ◽

Vol 11 ◽

Author(s):

Ruiting Lin ◽

Ruilian Chen ◽

Zhiqiang Chen ◽

Leihao Hu ◽

Wei Guo ◽

...

Keyword(s):

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Progression Free Survival ◽

Free Survival ◽

First Line Therapy ◽

Epidermal Growth ◽

Good Treatment Option ◽

Nsclc Patients ◽

First And Second Generation ◽

Egfr Tkis

The efficacy of first-and second-generation epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) in NSCLC patients with the EGFR L861Q mutation has been studied previously. However, there is little evidence on the efficacy of osimertinib in NSCLC patients with uncommon mutations. Here, we report the case of a 68-year-old man with advanced NSCLC with concurrent EGFR L861Q mutation as well as TP53 and RB1 mutations. The patient was treated with osimertinib as first-line therapy and achieved a remarkable progression-free survival of 15 months. His symptoms were significantly alleviated and the dose was well tolerated. The findings of the present study indicate that osimertinib might be a good treatment option for NSCLC patients with the L861Q mutation.

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Estrogen Receptor β1 Expression Patterns Have Different Effects on Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors’ Treatment Response in Epidermal Growth Factor Receptor Mutant Lung Adenocarcinoma

Frontiers in Oncology ◽

10.3389/fonc.2020.603883 ◽

2021 ◽

Vol 10 ◽

Author(s):

Lijuan Zhang ◽

Meng Tian ◽

Jiamao Lin ◽

Jianbo Zhang ◽

Haiyong Wang ◽

...

Keyword(s):

Estrogen Receptor ◽

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Lung Adenocarcinoma ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Pathway Activation ◽

Epidermal Growth ◽

Egfr Tkis

Estrogen receptor β (ERβ) can regulate cellular signaling through non-genomic mechanisms, potentially promoting resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). However, the mechanisms underlying the ERβ-mediated resistance to EGFR TKIs remain poorly understood. In this study, we investigated the role of the interaction between ERβ1 and ERβ5 in non-genomic signaling in lung adenocarcinoma. We established PC9 cell lines stably overexpressing ERβ1 or ERβ1/ERβ5. Immunofluorescence revealed that ERβ5 overexpression partly retained ERβ1 in the cytoplasm. Immunoblotting analyses revealed that EGFR pathway activation levels were higher in PC9/ERβ1/5 cells than those in PC9/ERβ1 or control PC9 cells. In the presence of estradiol, PI3K/AKT/mTOR pathway activation levels were higher in ERβ1/5-expressing cells than those in ERβ1-expressing cells. Additionally, PC9/ERβ1/5 cells were less prone to the cytotoxic and pro-apoptotic effects of gefitinib compared with PC9/ERβ1 or control PC9 cells. Cytoplasmic ERβ1 was associated with poor progression-free survival in lung cancer patients treated with EGFR TKIs. These results suggest that cytoplasmic ERβ1 was responsible for EGFR TKI resistance slightly through non-genomic mechanism in EGFR mutant lung adenocarcinoma.

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Critical Update and Emerging Trends in Epidermal Growth Factor Receptor Targeting in Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.11.890 ◽

2005 ◽

Vol 23 (11) ◽

pp. 2445-2459 ◽

Cited By ~ 505

Author(s):

José Baselga ◽

Carlos L. Arteaga

Keyword(s):

Epidermal Growth Factor Receptor ◽

Growth Factor ◽

Epidermal Growth Factor ◽

Tyrosine Kinase ◽

Kinase Inhibitors ◽

Growth Factor Receptor ◽

Egfr Gene ◽

Epidermal Growth ◽

Egfr Tkis ◽

Receptor Family

The epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase of the ErbB receptor family that is abnormally activated in many epithelial tumors. The aberrant activation of the EGFR leads to enhanced proliferation and other tumor-promoting activities, which provide a strong rationale to target this receptor family. There are two classes of anti-EGFR agents: monoclonal antibodies (MAbs) directed at the extracellular domain of the receptor and small molecule, adenosine triphosphate–competitive inhibitors of the receptor's tyrosine kinase. Anti-EGFR MAbs have shown antitumor activity in advanced colorectal carcinoma, squamous cell carcinomas of the head and neck, non–small-cell lung cancer (NSCLC) and renal cell carcinomas. The tyrosine kinase inhibitors (TKIs) have a partially different activity profile. They are active against NSCLC, and a specific EGFR inhibitor has shown improvement in survival. Recently, mutations and amplifications of the EGFR gene have been identified in NSCLC and predict for enhanced sensitivity to anti-EGFR TKIs. In addition to specific anti-EGFR TKIs, there are broader acting inhibitors such as dual EGFR HER-2 inhibitors and combined anti-pan-ErbB and antivascular endothelial growth factor receptor inhibitors. Current research efforts are directed at selecting the optimal dose and schedule and identifying predictive factors of response and resistance beyond EGFR gene mutations and/or amplifications. Finally, there is a need for improved strategies to integrate anti-EGFR agents with conventional therapies and to explore combinations with other molecular targeted approaches including other antireceptor therapies, receptor-downstream signaling transduction inhibitors, and targeted approaches interfering with other essential drivers of cancer, such as angiogenesis.

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