{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T05:08:43Z","timestamp":1788930523751,"version":"build-2803163510"},"reference-count":28,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T00:00:00Z","timestamp":1788912000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Oncol."],"abstract":"<jats:p>\n                    Third-generation epidermal growth factor receptor (\n                    <jats:italic>EGFR<\/jats:italic>\n                    ) tyrosine kinase inhibitors (EGFR-TKIs) have markedly improved outcomes for patients with\n                    <jats:italic>EGFR<\/jats:italic>\n                    -mutant non-small-cell lung cancer (NSCLC). However, acquired resistance remains a critical clinical challenge.Here, we present the case of a 62-year-old male with stage IIB poorly differentiated lung adenocarcinoma harboring an\n                    <jats:italic>EGFR<\/jats:italic>\n                    L858R mutation. The patient received adjuvant aumolertinib following surgical resection. Serial sampling and dynamic next-generation sequencing (NGS) revealed a sequential bypass resistance clone evolution trajectory in this patient: initial\n                    <jats:italic>MET<\/jats:italic>\n                    amplification was followed by the detection of a\n                    <jats:italic>BRAF<\/jats:italic>\n                    V600E mutation concurrent with\n                    <jats:italic>RET<\/jats:italic>\n                    fusion, while in the terminal phase,\n                    <jats:italic>MET<\/jats:italic>\n                    amplification re-emerged alongside a progressively increasing\n                    <jats:italic>TP53<\/jats:italic>\n                    variant allele frequency (VAF).Genotype-guided therapy adjustments yielded an 11-month progression-free survival (PFS) with aumolertinib plus savolitinib, whereas subsequent selpercatinib combined with chemotherapy provided only transient disease stabilization. Ultimately, the patient died of respiratory and circulatory failure due to progressive disease complicated by diffuse carcinomatous lymphangitis. Based on current evidence, we speculate that these bypass resistance alterations are driven by reactivation of the MAPK and PI3K\/AKT signaling cascades. The progressive increase in\n                    <jats:italic>TP53<\/jats:italic>\n                    mutant allele frequency was temporally concordant with the sequential emergence of bypass resistance mechanisms, suggesting an unfavorable prognosis. However, its utility in guiding therapeutic modifications requires further validation. This case illustrates that\n                    <jats:italic>EGFR<\/jats:italic>\n                    L858R-mutant lung adenocarcinoma can undergo stepwise clonal evolution of multiple bypass resistance mechanisms under aumolertinib selective pressure. Dynamic NGS profiling enables real-time tracking of resistant clone evolution to inform individualized treatment strategies.\n                  <\/jats:p>","DOI":"10.3389\/fonc.2026.1912859","type":"journal-article","created":{"date-parts":[[2026,9,9]],"date-time":"2026-09-09T04:40:08Z","timestamp":1788928808000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Dynamic clonal evolution of multiple bypass resistance mechanisms in EGFR-mutant lung adenocarcinoma: a case report"],"prefix":"10.3389","volume":"16","author":[{"given":"Qingyun","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of Oncology, Weifang People\u2019s Hospital (The First Affiliated Hospital of Shandong Second Medical University)","place":["Weifang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiaoyan","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of Oncology, Weifang People\u2019s Hospital (The First Affiliated Hospital of Shandong Second Medical University)","place":["Weifang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"15009","DOI":"10.1038\/nrdp.2015.9","article-title":"Non-small-cell lung cancer","volume":"1","author":"Gridelli","year":"2015","journal-title":"Nat Rev Dis Primers"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.2147\/dddt.s465238","article-title":"A visual analysis of the research dynamics in resistance to EGFR inhibitors for NSCLC","volume":"18","author":"Shao","year":"2024","journal-title":"Drug Des Devel Ther"},{"key":"B3","doi-asserted-by":"publisher","first-page":"1515","DOI":"10.3390\/cancers17091515","article-title":"Non-small cell lung cancer with epidermal growth factor receptor (EGFR) common mutations: New 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