[Studies and Progress of EGFR exon 20 Insertion Mutation in Non-small Cell Lung Cancer].
ABSTRACT: Lung cancer has the highest morbidity and mortality among malignant tumors worldwidely. Targeted therapy related to non-small cell lung cancer (NSCLC) is the research hotspot in recent year. The emergence of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) has brought a huge change in the treatment of patients with EGFR mutation. The patients with EGFR exon20 insertion are specific cohort in NSCLC. Reviewing the clinical researches to EGFR exon20 insertion mutation positive NSCLC, as well as summarizing character, testing methods and treatment, will provide a help for clinical application, bringing more benefits for patients at the same time.
Project description:PURPOSE:Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for approximately 4% of all EGFR mutations. Given the rarity of this mutation, its clinical outcomes are not fully established. Materials and Methods:Between 2009 and 2017, non-small cell lung cancer (NSCLC) patients who showed an exon 20 insertion were retrospectively reviewed for clinical characteristics and outcomes, including responses to chemotherapy (CTx) or targeted therapy. RESULTS:Of 3,539 NSCLC patients who harbored an activating EGFR mutation, 56 (1.6%) had an exon 20 insertion. Of the advanced NSCLC patients, 27 of 1,479 (1.8%) had an exon 20 insertion. The median overall survival was 29.4 months (95% confidence interval 9.3 to 49.6) for 27 advancedNSCLC patients. The 22 patientswho received systemic CTx achieved a 50.0% response rate and a 77.2% disease control rate, with 4.2 months of progressionfree survival. Six patients received EGFR tyrosine kinase inhibitors (TKIs). Three of the four patients that had only an exon 20 insertion showed progressive disease, while one showed stable disease. The othertwo patients had an exon 20 insertion and another EGFR mutation and achieved a partial response. CONCLUSION:The incidence of an exon 20 insertion mutation is rare in Korea and occasionally accompanied by other common EGFR mutations. Although the response to systemic CTx. in these patients is comparable to that of patients with other mutations, the response rate to firstor second-generation EGFR TKIs is quite low. Therefore, the development of a more efficient agent is urgently needed.
Project description:Inframe insertions of three or more base pairs in exon 20 of the epidermal growth factor receptor (EGFR) gene were among the first EGFR mutations to be identified as oncogenic drivers in non-small cell lung cancer (NSCLC). However, unlike the classical EGFR L858R point mutation or exon 19 deletions, which represent the majority of EGFR mutations in NSCLC, low frequency EGFR exon 20 insertion mutations are associated with de novo resistance to targeted EGFR inhibitors and correlate with a poor patient prognosis. Here, we review the developments over the last 5 years in which pre-clinical studies, including elucidation of the crystal structure of an EGFR exon 20 insertion mutant kinase, have revealed a unique mechanism of kinase activation and steric conformation that define the lack of response of these EGFR mutations to clinically approved EGFR inhibitors. The recent development of several novel small molecule compounds that selectively inhibit EGFR exon 20 insertions holds promise for future therapeutic options that will be effective for patients with this molecular subtype of NSCLC.
Project description:Exon 20 insertion (Ex20Ins) mutations are the third most prevalent epidermal growth factor receptor (EGFR) activating mutation and the most prevalent HER2 mutation in non-small cell lung cancer (NSCLC). Novel therapeutics for the patients with Ex20Ins mutations are urgently needed, due to their poor responses to the currently approved EGFR and HER2 inhibitors. Here we report the discovery of highly potent and broadly effective EGFR and HER2 Ex20Ins mutant inhibitors. The co-crystal structure of compound 1?b in complex with wild type EGFR clearly revealed an additional hydrophobic interaction of 4-fluorobenzene ring within a deep hydrophobic pocket, which has not been widely exploited in the development of EGFR and HER2 inhibitors. As compared with afatinib, compound 1?a exhibited superior inhibition of proliferation and signaling pathways in Ba/F3 cells harboring either EGFR or HER2 Ex20Ins mutations, and in the EGFR P772_H773insPNP patient-derived lung cancer cell line DFCI127. Our study identifies promising strategies for development of EGFR and HER2 Ex20Ins mutant inhibitors.
Project description:Epidermal growth factor receptor (EGFR) gene mutations (G719X, exon 19 deletions/insertions, L858R, and L861Q) predict favorable responses to EGFR tyrosine kinase inhibitors (TKIs) in advanced non-small cell lung cancer (NSCLC). However, EGFR exon 20 insertion mutations (~10% of all EGFR mutations) are generally associated with insensitivity to available TKIs (gefitinib, erlotinib, and afatinib). The basis of this primary resistance is poorly understood. We studied a broad subset of exon 20 insertion mutations, comparing in vitro TKI sensitivity with responses to gefitinib and erlotinib in NSCLC patients, and found that most are resistant to EGFR TKIs. The crystal structure of a representative TKI-insensitive mutant (D770_N771insNPG) reveals an unaltered adenosine triphosphate-binding pocket, and the inserted residues form a wedge at the end of the C helix that promotes the active kinase conformation. Unlike EGFR-L858R, D770_N771insNPG activates EGFR without increasing its affinity for EGFR TKIs. Unexpectedly, we find that EGFR-A763_Y764insFQEA is highly sensitive to EGFR TKIs in vitro, and patients whose NSCLCs harbor this mutation respond to erlotinib. Analysis of the A763_Y764insFQEA mutant indicates that the inserted residues shift the register of the C helix in the N-terminal direction, altering the structure in the region that is also affected by the TKI-sensitive EGFR-L858R. Our studies reveal intricate differences between EGFR mutations, their biology, and their response to EGFR TKIs.
Project description:A 20-year-old woman was diagnosed with stage 4 lung adenocarcinoma with an epidermal growth factor receptor (EGFR) exon 20 insertion gene mutation. Although the patient underwent chemotherapy, her lesions progressed. Liquid biopsy for EGFR T790M mutation showed negative results. After administering osimertinib, reduction of the lesions at the primary site was observed, and the patient's respiratory condition improved. Previous reports showing successful treatment of EGFR exon 20 insertion-positive lung adenocarcinoma with the standard osimertinib dose of 80 mg are limited. The present case demonstrated that osimertinib could be a possible treatment option for EGFR exon 20 insertion-positive lung adenocarcinoma.
Project description:Patients with non-small cell lung cancer (NSCLC) with activating epidermal growth factor receptor (EGFR) mutations (exon 19 deletions and L858R) benefit from EGFR tyrosine kinase inhibitors (TKIs). However, some researchers have reported that responses to TKIs differ by subtypes of EGFR exon 19 mutations. We retrospectively analyzed EGFR exon 19 deletion subtypes and their correlation with clinical outcomes of treatment with TKIs. A cohort of 2664 consecutive patients with NSCLC was enrolled. A total of 440 EGFR exon 19 deletions were defined as 39 subtypes. Among them, 158 patients with advanced lung adenocarcinoma with EGFR exon 19 deletion mutations received EGFR-TKIs. There were no significant differences in progression-free survival or overall survival among patients with non-LRE deletions, delE746, or delL747 (P = 0.463 and P = 0.464, respectively). Furthermore, two patients with EGFR exon19 insertion had durable response to EGFR-TKIs. In conclusion, EGFR exon 19 is highly fragile, resulting in many different deletion and insertion subtypes. There were no significant differences in clinical outcomes after TKI treatment across the different subtypes. It is necessary to attempt to identify all patients with exon 19 deletions so that they can be offered TKI treatment.
Project description:Lung cancer is the leading cause of cancer-related deaths worldwide. Non-small cell lung cancer (NSCLC) accounts for 80%-85% of all patients with lung cancer, the majority of patients with lung cancer at the time of diagnosis is in the advanced stage. The development of target therapy based on has changed the mode of treatment in patients with advanced NSCLC. In NSCLC, epidermal growth factor receptor mutation (EGFR) fusion with echinoderm microtubule-associated protein-like4-anaplastic lymphoma kinase (EML4-ALK) has been shown to be a powerful biomarker. It is well known that KRAS is also NSCLC one of the most common mutations in oncogenes, although more than 20 years ago KRAS mutation was found in NSCLC. At present, although there are many drugs used to treat NSCLC patients with KRAS mutation, there is no selective or specific inhibitor for the direct elimination of KRAS activity. NSCLC patients with KRAS mutation have poor responsiveness to most systemic therapy. However, individualized therapy for activated signaling pathways with targeted drugs has a good effect on the prognosis of NSCLC patients with KRAS mutation. In addition, the prognostic and predictive role of KRAS mutation in NSCLC remains unclear. In this review, we focus on the research progress of NSCLC with KRAS mutation, including molecular biology, clinicopathological features, prognosis and prediction of KRAS mutation, which will help to improve the understanding of NSCLC in KRAS mutation.?.
Project description:The most common event responsible for resistance to first- and second-generation (1st and 2nd) epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) is acquisition of T790M mutation. We examined whether T790M is related to clinicopathologic or prognostic factors in patients with relapse of EGFR mutant non-small cell lung cancer (NSCLC) after treatment with 1st or 2nd EGFR-TKIs. We retrospectively reviewed the T790M status and clinical characteristics of 73 patients with advanced or recurrent NSCLC who had been treated with EGFR-TKIs and undergone rebiopsy at Kurume University Hospital between March 2005 and December 2015. T790M mutation was more frequent in patients with EGFR exon 19 deletion mutation (63%, 26/41) than in those with L858R mutation (38%, 12/32) (p?=?0.035). The median total duration of 1st or 2nd EGFR-TKI treatment was significantly longer in patients with T790M mutation than in those without (15.3 months vs 8.1 months, p?<?0.001). Multivariate analysis revealed that the type of EGFR mutation and the total duration of EGFR-TKI treatment were significantly associated with T790M prevalence. Patients with EGFR exon 19 deletion mutation who receive long-term EGFR-TKI therapy show a high prevalence of T790M mutation. The present data are potentially important for clinical decision-making in NSCLC patients with EGFR mutation.
Project description:Researches on the inhibitors of programmed death-1 (PD-1) and programmed death-1 ligand (PD-L1) enjoy considerable breakthroughs in recent years, which has brought relative changes in the therapeutic model of non-small cell lung cancer (NSCLC) at an unexpected speed. However, it seems that PD-1/PD-L1 inhibitors are less effective in patients with epidermal growth factor receptor (EGFR) mutation than those without. Previous studies have shown that the expression rate of PD-L1 on tumor cells is correlated with the therapeutic effect of PD-1/PD-L1 inhibitors. Yet, there is no complete agreement on the effect of EGFR mutation on PD-L1 expression. In this review, relevant studies will be summarized with an expectation of making some contributions to basic researches and to the clinical treatment.