insertion mutations
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Cells ◽  
2021 ◽  
Vol 10 (12) ◽  
pp. 3561
Author(s):  
Ikei S. Kobayashi ◽  
Hollis Viray ◽  
Deepa Rangachari ◽  
Susumu S. Kobayashi ◽  
Daniel B. Costa

Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that can respond to multiple classes of approved EGFR-TKIs. We sought to characterize variants involving EGFR-D770 to EGFR-G770 position equivalence changes that structurally allow for response to irreversible 2nd generation EGFR-TKIs. Our group used preclinical models of EGFR exon 20 insertion mutations to probe representative 1st (erlotinib), 2nd (afatinib, dacomitinib), 3rd generation (osimertinib) and EGFR exon 20 insertion mutant-active (poziotinib, mobocertinib) TKIs; we also queried the available clinical literature plus our institutional database to enumerate clinical outcomes. EGFR-D770>GY and other EGFR insertions with a G770 equivalence were identified at a frequency of 3.96% in separate cohorts of EGFR exon 20 insertion mutated lung cancer (n = 429). Cells driven by EGFR-D770>GY were insensitive to erlotinib and osimertinib, displayed sensitivity to poziotinib and dacomitinib and were uniquely sensitive to afatinib and dacomitinib in comparison with other more typical EGFR exon 20 insertion mutations using proliferation and biochemical assays. Clinical cases with EGFR-G770 equivalence from the literature and our center mirrored the preclinical data, with radiographic responses and clinical benefits restricted to afatinib, dacomitinib, poziotinib and mobocertinib, but not to erlotinib or osimertinib. Although they are rare, at <4% of all exon 20 insertion mutations, EGFR-G770 equivalence exon 20 insertion mutations are sensitive to approved 2nd generation EGFR TKIs and EGFR exon 20 insertion mutant-active TKIs (mobocertinib and poziotinib). EGFR-D770>GY and other insertions with a G770 equivalence join EGFR-A763_Y764insFQEA as exon 20 insertion mutationsresponsive to approved EGFR TKIs beyond mobocertinib; this data should be considered for clinical care, genomic profiling reports and clinical trial elaboration.


Author(s):  
Xiuning Le ◽  
Robin Cornelissen ◽  
Marina Garassino ◽  
Jeffrey M. Clarke ◽  
Nishan Tchekmedyian ◽  
...  

PURPOSE Insertion mutations in Erb-b2 receptor tyrosine kinase 2 gene ( ERBB2 or HER2) exon 20 occur in 2%-5% of non–small-cell lung cancers (NSCLCs) and function as an oncogenic driver. Poziotinib, a tyrosine kinase inhibitor, was evaluated in previously treated patients with NSCLC with HER2 exon 20 insertions. METHODS ZENITH20, a multicenter, multicohort, open-label phase II study, evaluated poziotinib in patients with advanced or metastatic NSCLC. In cohort 2, patients received poziotinib (16 mg) once daily. The primary end point was objective response rate evaluated by independent review committee (RECIST v1.1); secondary outcome measures were disease control rate, duration of response, progression-free survival, and safety and tolerability. Quality of life was assessed. RESULTS Between October 2017 and March 2021, 90 patients with a median of two prior lines of therapy (range: 1-6) were treated. With a median follow-up of 9.0 months, objective response rate was 27.8% (95% CI, 18.9 to 38.2); 25 of 90 patients achieved a partial response. Disease control rate was 70.0% (95% CI, 59.4 to 79.2). Most patients (74%) had tumor reduction (median reduction 22%). Median progression-free survival was 5.5 months (95% CI, 3.9 to 5.8); median duration of response was 5.1 months (95% CI, 4.2 to 5.5). Clinical benefit was seen regardless of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations. Grade 3 or higher treatment-related adverse events included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Most patients had poziotinib dose reductions (76.7%), with median relative dose intensity of 71.5%. Permanent treatment discontinuation because of treatment-related adverse events occurred in 13.3% of patients. CONCLUSION Poziotinib demonstrates antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.


BMC Genomics ◽  
2021 ◽  
Vol 22 (1) ◽  
Author(s):  
Dongwei Li ◽  
Qitong Huang ◽  
Lei Huang ◽  
Jikai Wen ◽  
Jing Luo ◽  
...  

Abstract Background As a powerful tool, RNA-Seq has been widely used in various studies. Usually, unmapped RNA-seq reads have been considered as useless and been trashed or ignored. Results We develop a strategy to mining the full length sequence by unmapped reads combining with specific reverse transcription primers design and high throughput sequencing. In this study, we salvage 36 unmapped reads from standard RNA-Seq data and randomly select one 149 bp read as a model. Specific reverse transcription primers are designed to amplify its both ends, followed by next generation sequencing. Then we design a statistical model based on power law distribution to estimate its integrality and significance. Further, we validate it by Sanger sequencing. The result shows that the full length is 1556 bp, with insertion mutations in microsatellite structure. Conclusion We believe this method would be a useful strategy to extract the sequences information from the unmapped RNA-seq data. Further, it is an alternative way to get the full length sequence of unknown cDNA.


2021 ◽  
Author(s):  
Theresa B Loveless ◽  
Courtney K Carlson ◽  
Vincent J Hu ◽  
Catalina A Dentzel Helmy ◽  
Guohao Liang ◽  
...  

Genetically encoded DNA recorders noninvasively convert transient biological events into durable mutations in a cell's genome, allowing for the later reconstruction of cellular experiences using high-throughput DNA sequencing. Existing DNA recorders have achieved high-information recording, durable recording, prolonged recording over multiple timescales, multiplexed recording of several user-selected signals, and temporally resolved signal recording, but not all at the same time. We present a DNA recorder called peCHYRON (prime editing Cell HistorY Recording by Ordered iNsertion) that does. In peCHYRON, prime editor guide RNAs (pegRNAs) insert a variable triplet DNA sequence alongside a constant propagation sequence that deactivates the previous and activates the next step of insertion. This process results in the sequential accumulation of regularly spaced insertion mutations at a synthetic locus. Accumulated insertions are permanent throughout editing because peCHYRON uses a prime editor that avoids cutting both DNA strands, which risks deletions. Editing continues indefinitely because each insertion adds the complete sequence needed to initiate the next step. Constitutively expressed pegRNAs generate insertion patterns that support straightforward reconstruction of cell lineage relationships. Pulsed expression of different pegRNAs enables the reconstruction of pulse sequences, which may be coupled to biological stimuli for temporally-resolved multiplexed event recording.


Lung Cancer ◽  
2021 ◽  
Author(s):  
Lyudmila Bazhenova ◽  
Anna Minchom ◽  
Santiago Viteri ◽  
Joshua M. Bauml ◽  
Sai-Hong Ignatius Ou ◽  
...  

2021 ◽  
Vol 16 (10) ◽  
pp. S874
Author(s):  
P. Janne ◽  
M. Wang ◽  
P. Mitchell ◽  
J. Fang ◽  
W. Nian ◽  
...  

2021 ◽  
pp. 107815522110449
Author(s):  
Weisan Zhang ◽  
Xifeng Dong

Epidermal growth factor receptor gene exon 20 insertion mutations are seen in ∼4–12% of patients with epidermal growth factor receptor-mutant non-small cell lung cancer. However, there is no targeted therapy approved for the treatment of non-small cell lung cancer patients with these rare epidermal growth factor receptor mutations. Previous studies revealed that epidermal growth factor receptor gene exon 20 insertion mutations are unique in their ability to activate epidermal growth factor receptor without the typical structural changes associated with the common epidermal growth factor receptor mutations, reducing the clinical efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors currently approved for non-small cell lung cancer. Therefore, there is an urgent need to identify active epidermal growth factor receptor-tyrosine kinase inhibitors and other effective treatment strategies for non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations. Mobocertinib is a novel irreversible epidermal growth factor receptor-tyrosine kinase inhibitor that selectively targets epidermal growth factor receptor gene exon 20 insertion mutations. Preclinical study revealed that mobocertinib inhibited the viability of epidermal growth factor receptor gene exon 20 insertion mutations-driven patient-derived xenografts and murine orthotopic tumors more potently than traditional epidermal growth factor receptor-tyrosine kinase inhibitors. In a study recently published in Cancer Discovery, Gonzalvez et al. assessed the safety, tolerability, and antitumor efficacy of mobocertinib in metastatic non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations. They found that non-small cell lung cancer patients with epidermal growth factor receptor gene exon 20 insertion mutations can benefit from mobocertinib treatment. Additionally, the treatment-related toxicity of mobocertinib was manageable. These findings lay the foundation for the application of mobocertinib in epidermal growth factor receptor gene exon 20 insertion-mutated non-small cell lung cancer.


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