Next-generation sequencing of tyrosine kinase inhibitor-resistant non-small-cell lung cancers in patients harboring epidermal growth factor-activating mutations

Abstract

BackgroundThe aim of this study was to detect the epidermal growth factor receptor (EGFR)-activating mutations and other oncogene alterations in patients with non-small-cell lung cancers (NSCLC) who experienced a treatment failure in response to EGFR-tyrosine kinase inhibitors (TKIs) with a next generation sequencer.MethodsFifteen patients with advanced NSCLC previously treated with EGFR-TKIs were examined between August 2005 and October 2014. For each case, new biopsies were performed, followed by DNA sequencing on an Ion Torrent Personal Genome Machine (PGM) system using the Ion AmpliSeq Cancer Hotspot Panel version 2.ResultsAll 15 patients were diagnosed with NSCLC harboring EGFR-activating mutations (seven cases of exon 19 deletion, seven cases of L858R in exon 21, and one case of L861Q in exon 21). Of the 15 cases, acquired T790M resistance mutations were detected in 9 (60.0 %) patients. In addition, other mutations were identified outside of EGFR, including 13 cases (86.7 %) exhibiting TP53 P72R mutations, 5 cases (33.3 %) of KDR Q472H, and 2 cases (13.3 %) of KIT M541L.ConclusionsHere, we showed that next-generation sequencing (NGS) is able to detect EGFR T790M mutations in cases not readily diagnosed by other conventional methods. Significant differences in the degree of EGFR T790M and other EGFR-activating mutations may be indicative of the heterogeneity of disease phenotype evident within these patients. The co-existence of known oncogenic mutations within each of these patients may play a role in acquired EGFR-TKIs resistance, suggesting the need for alternative treatment strategies, with PCR-based NGS playing an important role in disease diagnosis.

KDR Mutation: A High-Frequency Rare Mutation and its Correlation with other Somatic Mutations in Indian Colorectal Cancer Patients

“…Another study reported a frequency of 38/123 patients (30.9%) with mutation in KDR gene in Malignant Pleural Mesothelioma [9]. It is noteworthy to mention here that, a study on non-small cell lung cancer reported high Q472H type of KDR mutation number in 33.3% patients [10] and in another study, it has been suggested to play a role of proto-oncogene in Lung Adeno-carcinoma [11]. Therefore, a high frequency (19.6%) of KDR mutation among the patients in our study may also indicate its role in developing cancer.…”

Cell-free DNA and next-generation sequencing in the service of personalized medicine for lung cancer

“…In addition to EGFR T790M, NGS revealed several other acquired resistance mutations, including mutations in TP53, KDR, and KIT [103], and compound EGFR mutations (i.e. more than one mutation in the EGFR tyrosine kinase domain) [104].…”

Cancer gene profiling in non-small cell lung cancers reveals activating mutations in JAK2 and JAK3 with therapeutic implications

“…While the germline mutations are often overlooked by previously published clinical sequencing studies [19], we analyzed our cohort for germline mutations with potential clinical implications. For example, KIT p.M541L mutation detected in 146 (16%, 146/932) tumors and KDR p.Q472H mutation in 5 (0.5%, 5/932) tumors are associated with resistance to EGFR inhibitors in NSCLCs [37]. The KDR p.Q472H germline mutation also confers increased sensitivity to antiangiogenesis treatment in melanomas [38].…”