Co‐mutational assessment of circulating tumour DNA (ctDNA) during osimertinib treatment for T790M mutant lung cancer

Xing, Puyuan; Han, Xiaohong; Wang, Sha; Liu, Yutao; Yang, Sheng; Hao, Xuezhi; Wang, Yan; Liu, Peng; Li, Junling; Wang, Lin; Chang, Lianpeng; Guan, Yanfang; Zhang, Zhishang; Wu, Di; Yao, Jiarui; Yi, Xin; Shi, Yuankai

doi:10.1111/jcmm.14565

Cited by 14 publications

(6 citation statements)

References 36 publications

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“…K754I conferred resistance against osimertinib in both the presence and absence of T790M; it was classified as having an intermediate effect in the afatinib arm. This result is compatible with a case report about a patient bearing T790M, in which osimertinib treatment led to loss of the T790M-encoding SNV but enriched that encoding K754I 57 .…”

Section: Maintextsupporting

confidence: 91%

Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing

Kim,

Oh,

Lee

et al. 2023

Preprint

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Variants of uncertain significance (VUS) hamper the clinical application of genetic information. For example, in treating lung cancer with tyrosine kinase inhibitors (TKIs), many epidermal growth factor receptor (EGFR) variants remain classified as VUS with respect to TKI sensitivity1,2. Such incomplete resistance profiles hinder clinicians from selecting optimal therapeutic agents3,4. A high-throughput approach that can evaluate the functional effects of single nucleotide variants (SNVs) could reduce the number of VUS. Here we introduce SynPrime, a method based on prime editing that enabled the generation and functional evaluation of 2,476 SNVs in theEGFRgene, including 99% of all possible variants in the canonical tyrosine kinase domain (exons 18 to 21). We determined resistance profiles of 95% (= 1,726/1,817) of all possible EGFR protein variants encoded in the whole tyrosine kinase domain (exons 18 to 24) against afatinib, osimertinib, and osimertinib in the presence of the co-occurring mutation T790M, in PC-9 cells. SynPrime, which uses direct sequencing of endogenous regions to identify SNVs, provided more accurate functional evaluations than a guide RNA abundance-based approach. Our study has the potential to substantially improve the precision of therapeutic choices in clinical settings and contribute to addressing the issue of VUS by being applied to other genes.

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Section: Maintextsupporting

confidence: 91%

Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing

Kim,

Oh,

Lee

et al. 2023

Preprint

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“…In addition, the mechanism of the difference in T790M mutation status when patients acquired resistance to Osimertinib remains unclear. The most likely explanation may be the genomic heterogeneity inherent in the tumor before the treatment with Osimertinib [26,27]. As previously reported, concomitant genomic alterations are widespread in lung cancer [28], and the T790M-positive and wild-type cell clones may co-exist in tumors at baseline levels or after acquired resistance to pre-EGFR TKI [29].…”

Section: Discussionmentioning

confidence: 91%

The Status of the EGFR T790M Mutation is associated with the Clinical Benefits of Osimertinib Treatment in Non-small Cell Lung Cancer Patients: A Meta-Analysis

Zhao

Li²,

Wang³

et al. 2020

J. Cancer

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Background and Purpose: Pervious studies have demonstrated that the loss of EGFR T790M after Osimertinib treatment may be the cause of Osimertinib resistance. Here, we conducted a meta-analysis to evaluate the association between the persistence of EGFR T790M and the clinical benefits of Osimertinib in non-small cell lung cancer (NSCLC) patients with baseline EGFR T790M mutation. Experimental design and Methods: PUBMED, EMBASE, and Cochrane databases were searched for eligible studies that provided the survival outcomes including overall survival (OS), progression-free survival (PFS) or time to discontinuation (TTD) data for each patient treated with Osimertinib with the status of the T790M mutation tested after Osimertinib resistance. The hazard ratios (HRs) and their 95% confidence intervals (CI) were calculated for each study. Results: In total, eight eligible studies were included in the analysis, among which six studies provided the data on PFS, and the other two studies provided the TTD data. Overall, 312 patients (151 patients with the persistence of T790M) were identified. The persistence of T790M was associated with longer PFS (HR, 0.40; 95% CI, 0.19-0.84; P=0.01) and TTD (HR, 0.54; 95% CI, 0.39-0.76; P=0.0004). Furthermore, overall analysis the survival outcomes including PFS and TTD subgroups also showed preferable clinical benefits for patients with the T790M persistence (HR, 0.57; 95%CI, 0.45-0.73; P<0.00001). Conclusions: Our findings confirm the persistence of T790M is associated with the clinical benefits of Osimertinib in NSCLC patients with baseline EGFR T790M mutation treated with Osimertinib.

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“…The tumor heterogeneity was attributed to both genetic and non‐genetic mechanisms acting at various intervals for targeted drugs, including EGFR‐TKIs in NSCLC patients with EGFR mutations 26,27 . TMB, CIS, and MATH scores help to evaluate intratumor genetic heterogeneity, which is closely related to drug resistance and poor outcomes in patients with lung cancer harboring EGFR mutations 28–33 . In this study, gefitinib‐resistant cells showed diverse CIS, TMB, and MATH scores compared with dacomitinib‐induced resistant cells, suggesting that the wide range of inhibitory activity of dacomitinib might prevent gene alterations and yield a low proportion of sub‐clones with EGFR ‐T790M mutation 23 .…”

Section: Discussionmentioning

confidence: 74%

Heterogeneity among tumors with acquired resistance to EGFR tyrosine kinase inhibitors harboring EGFR‐T790M mutation in non‐small cell lung cancer cells

et al. 2022

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EGFR‐T790M mutation is a major mechanism underlying acquired resistance to first‐ and second‐generation EGFR tyrosine kinase inhibitors (EGFR‐TKIs) in lung cancer with mutated EGFR. However, differences in the biological characteristics of T790M tumors based on treatment regimens with each generation of EGFR‐TKI are not fully understood. We established cell lines with acquired resistance harboring EGFR‐T790M mutation derived from xenograft tumors treated with each generation of EGFR‐TKI and examined their biological characteristics with respect to third‐generation EGFR‐TKI osimertinib sensitivity. Second‐generation EGFR‐TKI dacomitinib‐resistant cells with T790M‐exhibited higher sensitivity to osimertinib than first‐generation EGFR‐TKI gefitinib‐resistant cells with T790M via inhibition of AKT and ERK signaling and promotion of apoptosis. Furthermore, gefitinib‐resistant cells showed enhanced intratumor heterogeneity accompanied by genomic instability and activation of alternative resistance mechanisms compared with dacomitinib‐resistant cells; this suggests that the maintenance of EGFR dependency after acquiring resistance might depend on the type of EGFR‐TKI. Our results demonstrate that the progression of tumor heterogeneity via both genetic and non‐genetic mechanisms might affect osimertinib sensitivity in tumors with acquired resistance harboring EGFR‐T790M mutation.

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Co‐mutational assessment of circulating tumour DNA (ctDNA) during osimertinib treatment for T790M mutant lung cancer

Cited by 14 publications

References 36 publications

Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing

Saturation resistance profiling of EGFR variants against tyrosine kinase inhibitors using prime editing

The Status of the EGFR T790M Mutation is associated with the Clinical Benefits of Osimertinib Treatment in Non-small Cell Lung Cancer Patients: A Meta-Analysis

Heterogeneity among tumors with acquired resistance to EGFR tyrosine kinase inhibitors harboring EGFR‐T790M mutation in non‐small cell lung cancer cells

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