scholarly journals Molecular and Clinical Features of EGFR-TKI-Associated Lung Injury

2021 ◽  
Vol 22 (2) ◽  
pp. 792
Author(s):  
Tohru Ohmori ◽  
Toshimitsu Yamaoka ◽  
Koichi Ando ◽  
Sojiro Kusumoto ◽  
Yasunari Kishino ◽  
...  
Keyword(s):  
Lung Injury ◽  
Tyrosine Kinase ◽  
Performance Status ◽  
Cytotoxic Agents ◽  
Egfr Mutations ◽  
Poor Performance Status ◽  
Chronic Obstructive ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

The tyrosine kinase activity of epidermal growth factor receptors (EGFRs) plays critical roles in cell proliferation, regeneration, tumorigenesis, and anticancer resistance. Non-small-cell lung cancer patients who responded to EGFR-tyrosine kinase inhibitors (EGFR-TKIs) and obtained survival benefits had somatic EGFR mutations. EGFR-TKI-related adverse events (AEs) are usually tolerable and manageable, although serious AEs, including lung injury (specifically, interstitial lung disease (ILD), causing 58% of EGFR-TKI treatment-related deaths), occur infrequently. The etiopathogenesis of EGFR-TKI-induced ILD remains unknown. Risk factors, such as tobacco exposure, pre-existing lung fibrosis, chronic obstructive pulmonary disease, and poor performance status, indicate that lung inflammatory circumstances may worsen with EGFR-TKI treatment because of impaired epithelial healing of lung injuries. There is limited evidence from preclinical and clinical studies of the mechanisms underlying EGFR-TKI-induced ILD in the available literature. Herein, we evaluated the relationship between EGFR-TKIs and AEs, especially ILD. Recent reports on mechanisms inducing lung injury or resistance in cytokine-rich circumstances were reviewed. We discussed the relevance of cytotoxic agents or immunotherapeutic agents in combination with EGFR-TKIs as a potential mechanism of EGFR-TKI-related lung injury and reviewed recent developments in diagnostics and therapeutics that facilitate recovery from lung injury or overcoming resistance to anti-EGFR treatment.

Impact of HER2 aberrations on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS STUDY subset analysis.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9056-9056 ◽  
Author(s):  
Hiroe Kayatani ◽  
Keisuke Aoe ◽  
Kadoaki Ohashi ◽  
Hiroshige Yoshioka ◽  
Akihiro Bessho ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Egfr Mutations ◽  
Her2 Protein ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Mutant ◽  
Egfr Mutated ◽  
Egfr Tki ◽  
Egfr Tkis

9056 Background: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are a key treatment for EGFR-mutated non-small-cell lung carcinoma (NSCLC). To date, a biomarker to predict whether NSCLC will exhibit a short- or long-term response to first- or second-generation EGFR-TKIs has not been established for clinical use. Human epidermal growth factor receptor-2 (HER2) aberrations are mechanisms for acquired resistance to EGFR-TKIs; however, their impact on EGFR-TKI therapy outcomes in EGFR-mutant NSCLC has not yet been systematically evaluated. Methods: Patients with advanced NSCLC were prospectively registered from more than 35 institutes (HER2-CS STUDY UMIN 000017003). EGFR mutations or anaplastic lymphoma kinase gene translocations were assessed at each institution using a commercially approved test. HER2 protein expression levels were determined by immunohistochemistry (IHC) using the Ventana I-VIEW PATHWAY anti-HER-2/neu (4B5). The IHC status scoring system applied to gastric cancer was used. Results: Of 1,126 screened patients with NSCLC, 354 (31.8%) had EGFR-mutated tumors, and the HER2 protein statuses were as follows: IHC0 (n = 71, 26%), IHC1+ (n = 148, 53%), IHC2+ (n = 51, 18%), and IHC3+ (n = 7, 3%). The patients’ demographics were almost identical in those with lung tumors harboring EGFR mutations and HER2-IHC2+/3+ (group P) or EGFR mutations and HER2-IHC0/1 (group N). The EGFR-TKI response rates were not different between these groups (Table). However, group P showed significantly shorter time to EGFR-TKI treatment failure than group N (median 19.1 vs. 13.3 months; log rank p = 0.038). Conclusions: These data from a large prospective cohort show that HER2 protein expression in EGFR-mutant NSCLC may have a negative impact on the effect of EGFR-TKIs. A clinical trial of EGFR/HER2-TKIs (e.g., afatinib) is warranted for this population. [Table: see text]

Identification of RET fusion as mechanisms of resistance to EGFR tyrosine-kinase inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21074-e21074
Author(s):  
Zhongxing Bing ◽  
Weiran Wang ◽  
Danhua Wang ◽  
Tonghui Ma
Keyword(s):  
Lung Cancer ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Kinase Inhibitors ◽  
Next Generation Sequencing Data ◽  
Egfr Mutations ◽  
Egfr Tyrosine Kinase ◽  
Egfr Tyrosine Kinase Inhibitors ◽  
Egfr Tki ◽  
Egfr Tkis

e21074 Background: Responses to EGFR-targeted therapy are generally temporary, due to inevitable drug resistance. Although RET fusions have been identified in resistant EGFR-mutant non–small cell lung cancer (NSCLC), their characteristics acquired resistance to EGFR tyrosine-kinase inhibitors (TKIs) are rarely investigated. Methods: We retrospectively reviewed next-generation sequencing data of EGFR+ lung cancer patients, and 8 patients were identified coexisting of EGFR mutations and RET fusion. Their treatment history was collected. Results: The co-occurrence of RET fusion with EGFR oncogenic variations was observed in eight patients, and all of the 8 patients have received previous EGFR-TKI treatment. EGFR mutations were including 4 L858R mutations, 4 exon 19 deletions, and 6 T790M mutations. And the partner genes of RET identified by NGS were including TRIM33 (2/8), GPRC6A (1/8), TLN1 (1/8), KIAA1598 (1/8), SPECC1 (1/8), TRIM24 (1/8) and CCDC6 (1/8). The allelic fractions (AFs) of first-generation EGFR-TKI sensitizing mutations were higher than AFs of EGFR T790M mutations as well as AFs of RET fusion. These RET fusions are fused with rare partner genes, rather than the most common KIF5B in lung cancer. Conclusions: This study extended the knowledge of RET fusion as resistance mechanism to EGFR TKIs in lung cancer. The detection of RET fusions may uncover potential resistance mechanisms of EGFR TKIs, which might inform therapeutic strategies, such as combination-therapy approaches.[Table: see text]

Treating Patients With EGFR-Sensitizing Mutations: First Line or Second Line—Is There a Difference?

2013 ◽  
Vol 31 (8) ◽  
pp. 1081-1088 ◽  
Author(s):  
Tony Mok ◽  
Jin-Ji Yang ◽  
Kwok-Chi Lam
Keyword(s):  
Drug Exposure ◽  
Tumor Response ◽  
Kinase Inhibitor ◽  
Performance Status ◽  
Egfr Mutations ◽  
Poor Performance Status ◽  
Second Line ◽  
First Line ◽  
The Impact ◽  
Egfr Tki

First-line epidermal growth factor receptor tyrosine kinase inhibitor (EGFR TKI) is a standard treatment for patients with activating EGFR mutations. Six randomized studies have demonstrated consistent improvement in tumor response rate and progression-free survival over platinum-based combination chemotherapy. The only reason to consider EGFR TKI as second-line therapy is that none of the six comparative studies has shown improvement in overall survival, which can be explained by the high proportion of patients from the chemotherapy arm crossing over to the EGFR TKI arm on progression. It is true that patients with EGFR mutations may benefit from second-line EGFR TKI therapy, but we cannot conclude that the benefit is either equal to or inferior to first-line EGFR TKI therapy. To date, there are no direct comparative data between first- and second-line EGFR TKI in patients with activating EGFR mutations. Tumor response rates to second-line EGFR TKI have been inconsistent, which could potentially be explained by the impact of first-line chemotherapy on the abundance of tumor cells with activating EGFR mutations. However, numerous arguments, including assurance on drug exposure, improvement in quality of life, better tolerance by patients with poor performance status, and deferral of whole-brain radiation therapy for patients with brain metastasis, support the general application of first-line EGFR TKI.

Drug Combinatorial Therapies for the Treatment of KRAS Mutated Lung Cancers

2019 ◽  
Vol 19 (23) ◽  
pp. 2128-2142 ◽  
Author(s):  
Hao He ◽  
Chang Xu ◽  
Zhao Cheng ◽  
Xiaoying Qian ◽  
Lei Zheng
Keyword(s):  
Lung Cancer ◽  
Adjuvant Therapy ◽  
Combination Therapy ◽  
Clinical Benefit ◽  
Poor Prognosis ◽  
Egfr Mutations ◽  
Kras Mutations ◽  
Lung Cancers ◽  
Egfr Tki ◽  
Egfr Tkis

: KRAS is the most common oncogene to be mutated in lung cancer, and therapeutics directly targeting KRAS have proven to be challenging. The mutations of KRAS are associated with poor prognosis, and resistance to both adjuvant therapy and targeted EGFR TKI. EGFR TKIs provide significant clinical benefit for patients whose tumors bear EGFR mutations. However, tumors with KRAS mutations rarely respond to the EGFR TKI therapy. Thus, combination therapy is essential for the treatment of lung cancers with KRAS mutations. EGFR TKI combined with inhibitors of MAPKs, PI3K/mTOR, HDAC, Wee1, PARP, CDK and Hsp90, even miRNAs and immunotherapy, were reviewed. Although the effects of the combination vary, the combined therapeutics are one of the best options at present to treat KRAS mutant lung cancer.

scholarly journals Global proteome and phosphoproteome alterations in third generation EGFR TKI resistance reveal drug targets to circumvent resistance

2020 ◽  
Author(s):  
Xu Zhang ◽  
Tapan K. Maity ◽  
Karen E. Ross ◽  
Yue Qi ◽  
Constance M. Cultraro ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lung Adenocarcinoma ◽  
Signaling Pathways ◽  
Egfr Mutations ◽  
Altered Expression ◽  
Mesenchymal Transition ◽  
Tki Resistance ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Resistant Cells

AbstractLung cancer is the leading cause of cancer mortality worldwide. The treatment of lung cancer patients harboring mutant EGFR with orally administered EGFR TKIs has been a paradigm shift. Osimertinib and rociletinib are 3rd generation irreversible EGFR TKIs targeting the EGFR T790M mutation. Osimertinib is the current standard care for patients with EGFR mutations due to increased efficacy, lower side effects, and enhanced brain penetrance. Unfortunately, all patients develop resistance. Genomic approaches have primarily been used to interrogate resistance mechanisms. Here, we have characterized the proteome and phosphoproteome of a series of isogenic EGFR mutant lung adenocarcinoma cell lines that are either sensitive or resistant to these drugs. To our knowledge, this is the most comprehensive proteomic dataset resource to date to investigate 3rd generation EGFR TKI resistance in lung adenocarcinoma. We have interrogated this unbiased global quantitative mass spectrometry dataset to uncover alterations in signaling pathways, reveal a proteomic signature of epithelial mesenchymal transition (EMT) and identify kinases and phosphatases with altered expression and phosphorylation in TKI resistant cells. Decreased tyrosine phosphorylation of key sites in the phosphatase SHP2 suggests its inhibition resulting in inhibition of RAS/MAPK and activation of PI3K/AKT pathways. Furthermore, we performed anticorrelation analyses of this phosphoproteomic dataset with the published drug-induced P100 phosphoproteomic datasets from the Library of Integrated Network-Based Cellular Signatures (LINCS) program to predict drugs with the potential to overcome EGFR TKI resistance. We identified dactolisib, a PI3K/mTOR inhibitor, which in combination with osimertinib overcomes resistance both in vitro and in vivo.One Sentence SummaryGlobal quantitative proteome and phosphoproteome analyses to examine altered signaling pathways in isogenic 3rd generation EGFR TKI sensitive and resistant cells.

scholarly journals Clinical Characteristics and Survival Outcomes for Non-Small-Cell Lung Cancer Patients with Epidermal Growth Factor Receptor Double Mutations

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Min Peng ◽  
Yi Ming Weng ◽  
Hua Li Liu ◽  
Gui Fang Yang ◽  
Yi Yao ◽  
...  
Keyword(s):  
Epidermal Growth Factor Receptor ◽  
Growth Factor ◽  
Epidermal Growth Factor ◽  
Growth Factor Receptor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Epidermal Growth ◽  
Tki Treatment ◽  
Egfr Tki ◽  
Egfr Tkis

Multiple randomized clinical trials have demonstrated that epidermal growth factor receptor (EGFR) exon 19 deletion (19Del) and exon 21 L858R mutation (L858R) are highly correlated with sensitivity to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) treatment in non-small-cell lung cancer (NSCLC). A mutation in exon 20 (T790M) is reportedly associated with resistance to EGFR-TKIs. However, few studies have focused on patients harboring double mutations in these 3 mutation sites. In this retrospective study, forty-five patients (45/2546, 1.7%) harbored double mutations of 19Del, L858R, and T790M. Twenty-four patients with EGFR double mutations received EGFR-TKI therapy. Clinical characteristics of these patients, including the response to EGFR-TKIs and progression-free survival outcome for EGFR-TKI treatment (PFS-TKI), were analyzed. Patients with EGFR double mutations were more likely to be nonsmokers, have an Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0-1, have adenocarcinoma, and be at stage III-IV. The ORR, DCR, and median PFS-TKI in patients harboring EGFR double mutations were lower than in patients with a single EGFR-activating mutation. The differences in ORR and DCR were statistically insignificant between the 3 groups. Patients with double mutations of 19Del and T790M had longer PFS-TKIs than patients in the other 2 groups.

scholarly journals Concurrent Genetic Alterations and Other Biomarkers Predict Treatment Efficacy of EGFR-TKIs in EGFR-Mutant Non-Small Cell Lung Cancer: A Review

2020 ◽  
Vol 10 ◽  
Author(s):  
Yijia Guo ◽  
Jun Song ◽  
Yanru Wang ◽  
Letian Huang ◽  
Li Sun ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Treatment Efficacy ◽  
Genetic Alterations ◽  
Small Cell ◽  
Egfr Mutations ◽  
Small Cell Lung ◽  
Egfr Mutant ◽  
Egfr Tki ◽  
Egfr Tkis ◽  
Gene Alterations

Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) greatly improve the survival and quality of life of non-small cell lung cancer (NSCLC) patients with EGFR mutations. However, many patients exhibit de novo or primary/early resistance. In addition, patients who initially respond to EGFR-TKIs exhibit marked diversity in clinical outcomes. With the development of comprehensive genomic profiling, various mutations and concurrent (i.e., coexisting) genetic alterations have been discovered. Many studies have revealed that concurrent genetic alterations play an important role in the response and resistance of EGFR-mutant NSCLC to EGFR-TKIs. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on EGFR-TKI treatment efficacy is necessary. Further exploration of other biomarkers that can predict EGFR-TKI efficacy will help clinicians identify patients who may not respond to TKIs and allow them to choose appropriate treatment strategies. Here, we review the literature on specific gene alterations that coexist with EGFR mutations, including common alterations (intra-EGFR [on target] co-mutation, TP53, PIK3CA, and PTEN) and driver gene alterations (ALK, KRAS, ROS1, and MET). We also summarize data for other biomarkers (e.g., PD-L1 expression and BIM polymorphisms) associated with EGFR-TKI efficacy.

Impact of HER2 expression on EGFR-TKI treatment outcomes in lung tumors harboring EGFR mutations: A HER2-CS study subset analysis

Lung Cancer ◽  
2020 ◽  
Vol 150 ◽  
pp. 83-89
Author(s):  
Kadoaki Ohashi ◽  
Kiichiro Ninomiya ◽  
Hiroshige Yoshioka ◽  
Akihiro Bessho ◽  
Takuo Shibayama ◽  
...  
Keyword(s):  
Treatment Outcomes ◽  
Lung Tumors ◽  
Egfr Mutations ◽  
Her2 Expression ◽  
Subset Analysis ◽  
Tki Treatment ◽  
Egfr Tki
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