Details

Autor(en) / Beteiligte

• Roper, Nitin
• Brown, Anna-Leigh
• Wei, Jun S.
• Pack, Svetlana
• Trindade, Christopher
• Kim, Chul
• Restifo, Olivia
• Gao, Shaojian
• Sindiri, Sivasish
• Mehrabadi, Farid
• El Meskini, Rajaa
• Ohler, Zoe Weaver
• Maity, Tapan K.
• Venugopalan, Abhilash
• Cultraro, Constance M.
• Akoth, Elizabeth
• Padiernos, Emerson
• Chen, Haobin
• Kesarwala, Aparna
• Smart, DeeDee K.
• Nilubol, Naris
• Rajan, Arun
• Piotrowska, Zofia
• Xi, Liqiang
• Raffeld, Mark
• Panchenko, Anna R.
• Sahinalp, Cenk
• Hewitt, Stephen
• Hoang, Chuong D.
• Khan, Javed
• Guha, Udayan

Titel

Clonal Evolution and Heterogeneity of Osimertinib Acquired Resistance Mechanisms in EGFR Mutant Lung Cancer

Ist Teil von

• Cell reports. Medicine, 2020-04, Vol.1 (1), p.100007, Article 100007

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• Clonal evolution of osimertinib-resistance mechanisms in EGFR mutant lung adenocarcinoma is poorly understood. Using multi-region whole-exome and RNA sequencing of prospectively collected pre- and post-osimertinib-resistant tumors, including at rapid autopsies, we identify a likely mechanism driving osimertinib resistance in all patients analyzed. The majority of patients acquire two or more resistance mechanisms either concurrently or in temporal sequence. Focal copy-number amplifications occur subclonally and are spatially and temporally separated from common resistance mutations such as EGFR C797S. MET amplification occurs in 66% (n = 6/9) of first-line osimertinib-treated patients, albeit spatially heterogeneous, often co-occurs with additional acquired focal copy-number amplifications and is associated with early progression. Noteworthy osimertinib-resistance mechanisms discovered include neuroendocrine differentiation without histologic transformation, PD-L1, KRAS amplification, and ESR1-AKAP12, MKRN1-BRAF fusions. The subclonal co-occurrence of acquired genomic alterations upon osimertinib resistance will likely require targeting multiple resistance mechanisms by combination therapies. [Display omitted] Two or more subclonal genomic alterations are acquired upon osimertinib resistance66% of first-line osimertinib-treated patients acquire MET amplificationAcquired focal copy-number alterations are associated with early progressionNeuroendocrine differentiation with NSCLC histology is revealed by RNA-seq analysis Roper et al. perform multi-region whole-exome and RNA sequencing of pre- and post-resistant tumors from EGFR mutant lung cancer patients treated with osimertinib. They uncover the subclonal co-occurrence of acquired genomic alterations upon osimertinib resistance suggesting combination first-line therapies may prevent or delay key resistance mechanisms.