Molecular Characteristics of the Uncommon EGFR Exon 21 T854A Mutation and Response to Osimertinib in Patients With Non-Small Cell Lung Cancer

Zhang, Lihong; Yang, Xia; Zhou, Ming; Shi, Jie; Lv, Xin; Li, Wei; Yuan, Bo; Che, Yang; Liu, Boxuan; Liu, Shiyuan; Wei, Qingbo; Gu, Dejian; Chen, Rongrong; Yuan, Mingming; Cui, Jean; Ou, Sai‐Hong Ignatius; Yang, Shuanying

doi:10.1016/j.cllc.2021.12.008

Cited by 13 publications

(8 citation statements)

References 18 publications

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“…S3E-F). Notably, EGFR T854A has previously been associated with resistance to EGFR inhibitors [48][49][50] . HER2 T862A is also resistant to BI-1622, a novel HER2 inhibitor shown to directly interact with S783 51 .…”

Section: Discussionmentioning

confidence: 99%

Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer

Marín

Mamun

Akamatsu

et al. 2022

Preprint

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HER2 mutations drive the growth of a subset of breast cancers and are targeted with HER2 tyrosine kinase inhibitors (TKIs) such as neratinib. However, acquired resistance is common and limits the durability of clinical responses. Most HER2-mutant breast cancers progressing on neratinib-based therapy acquire secondary mutations in HER2. Apart from the HER2T798I gatekeeper mutation, whether these secondary HER2 mutations are causal to neratinib resistance is not known. We show herein that secondary acquired HER2T862A and HER2L755S mutations promote resistance to HER2 TKIs via enhanced HER2 activation and impaired neratinib binding. While cells expressing each acquired HER2 mutation alone were sensitive to neratinib, expression of acquired double mutations enhanced HER2 signaling and reduced neratinib sensitivity in 2D and 3D assays. Computational structural modeling suggested that secondary HER2 mutations stabilize the HER2 active state and reduce neratinib binding affinity. Cells expressing double HER2 mutations exhibited resistance to most HER2 TKIs but retained sensitivity to mobocertinib and poziotinib. Double-mutant cells showed enhanced MEK/ERK signaling which was blocked by combined inhibition of HER2 and MEK, providing a potential treatment strategy to overcome resistance to HER2 TKIs in HER2-mutant breast cancer.

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Section: Discussionmentioning

confidence: 99%

Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer

Marín

Mamun

Akamatsu

et al. 2022

Preprint

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“…Our in vivo assay suggests second-and thirdgeneration EGFR-TKIs may achieve a superior treatment outcome than rst-generation EGFR-TKIs, and we aim to con rm this in a clinical setting. V843I has been identi ed as a lung cancer predisposing mutation, and cells with L858R plus V843I appeared to be more sensitive to second-generation than rst-generation EGFR-TKIs (33); L858R plus T854A has been reported respond to osimertinib (34). Two Chinese LUAD patients harboring L858R plus G873E mutations was reported to achieve a PFS of 146 days and 120 days, with the treatment of erlotinib and ge tinib respectively [34].…”

Section: Discussionmentioning

confidence: 99%

“…V843I has been identi ed as a lung cancer predisposing mutation, and cells with L858R plus V843I appeared to be more sensitive to second-generation than rst-generation EGFR-TKIs (33); L858R plus T854A has been reported respond to osimertinib (34). Two Chinese LUAD patients harboring L858R plus G873E mutations was reported to achieve a PFS of 146 days and 120 days, with the treatment of erlotinib and ge tinib respectively [34]. Recently, V765l and E709A plus G719A are also reported more sensitive to second-generation EGFR-TKIs (35,36).…”

Section: Discussionmentioning

confidence: 99%

Profiling of Driver Mutations Identified Rare Compound Mutations Sensitive to Second-generation EGFR-TKI in Lung Adenocarcinoma Patients

Zhang

Guan

et al. 2022

Preprint

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Background: Lung adenocarcinoma (LUAD) is the most predominant histological subtype of lung cancer characterized by driver mutations detected in a substantial proportion of the cases. Tyrosine kinase inhibitors (TKIs) are standard care for the patients with these mutations. In this study, we evaluated the efficiency of an NGS-based 8-gene test in selecting TKIs-sensitive Chinese LUAD patients who are treatment-naïve. Material and methods: Targeted sequencing covering the hotspot regions of eight LUAD driver genes was performed across 853 treatment-naïve LUAD patients. Logistic regression analysis was used to determine the factors associated with presence of these mutations. Genetically modified LUAD PC9 cells were established to evaluated the sensitivity of selected EGFRcompound mutations to different EGFR-TKIs in-vivo. Results: A total of 574 single nucleotide variants, 270 InDels, 88 amplifications, and 87 rearrangements were identified in this study, with EGFR and KRAS being the most frequently mutated genes. Females, mostly life-long non-smokers, had significantly higher EGFRmutation rates than males and had a T>A conversion signature, for which the etiological factor is still unknown. Males, primarily smokers, more frequently had KRAS mutations and a smoking-associated signature of C>A conversions. Rare EGFR compound mutations identified in this study (Exon19del plus L747S/I744V and L858R plus V843I/T854A/G873) conferred genetically modified PC9 cells, constantly and consistently, more sensitive to second-generation EGFR-TKI afatinib in-vivo. Conclusion: Over 70% of Chinese treatment-naïve LUAD patients are TKIs-targetable. Patients with rare EGFR compound mutations might conside second-generation EGFR-TKIs for treatment.

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“…Other rare secondary mutations, such as L747S ( 41 ), D761Y ( 42 ), and T854A ( 43 ), have also been reported to be associated with gefitinib or erlotinib resistance. Due to the low incidence of these mutations, there are few in vitro studies and case reports showing whether Osimertinib is effective against these rare mutations ( 44 – 47 ).…”

Section: Drug Resistance Mechanisms and Progress In The Use Of First-...mentioning

confidence: 99%

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

et al. 2022

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According to global cancer data, lung cancer was the leading cause of cancer-related death in 2020. With the diversification of treatment strategies, the survival outcomes of patients with advanced lung cancer have improved significantly, but the 5-year overall survival rate remains <20%. Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment for lung adenocarcinoma patients with EGFR-sensitive mutations; however, acquired drug resistance is inevitable. Osimertinib (a third-generation EGFR inhibitor) is the most commonly used drug for cancers with a secondary T790M mutation. Unfortunately, acquired drug resistance against third-generation drugs still emerges. The C797s mutation is the primary acquired resistance mechanism against Osimertinib. Research on fourth-generation EGFR-TKI drugs with a C797s mutation is currently at various experimental stages, and no drug has been approved for clinical use. In addition to the resistance mechanisms described above, HER2 amplification, MET amplification, PIK3A mutation, KRAS mutation, BRAF mutation, transformation to small cell lung cancer, transformation to lung squamous cell carcinoma, and EMT have been reported as mechanisms of acquired drug resistance to first-, second-and third-generation EGFR-TKIs. These mechanisms are noted in a relatively high proportion of tumors, but treatment options are limited. In recent years, immunotherapy has made progress in the treatment of several cancers, including advanced EGFR-mutated non-small cell lung cancer (NSCLC). Due to the relatively high frequency of EGFR mutation in patients with lung adenocarcinoma in China, an increased number of patients develop EGFR-TKI resistance, and subsequent treatment options are critical. This article reviews the mechanisms of drug resistance to different EGFR-TKIs and treatment progression, providing ideas for the follow-up treatment for EGFR-resistant patients.

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Molecular Characteristics of the Uncommon EGFR Exon 21 T854A Mutation and Response to Osimertinib in Patients With Non-Small Cell Lung Cancer

Cited by 13 publications

References 18 publications

Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer

Acquired secondary HER2 mutations enhance HER2/MAPK signaling and promote resistance to HER2 kinase inhibition in HER2-mutant breast cancer

Profiling of Driver Mutations Identified Rare Compound Mutations Sensitive to Second-generation EGFR-TKI in Lung Adenocarcinoma Patients

Drug resistance mechanisms and progress in the treatment of EGFR‑mutated lung adenocarcinoma (Review)

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