<i>EGFR</i> Fusions as Novel Therapeutic Targets in Lung Cancer

Konduri, Kartik; Gallant, Jean‐Nicolas; Chae, Young Kwang; Giles, Francis J.; Gitlitz, Barbara J.; Gowen, Kyle; Ichihara, Eiki; Owonikoko, Taofeek K.; Peddareddigari, Vijay; Ramalingam, Suresh S.; Reddy, Satyanarayan K.; Eaby-Sandy, Beth; Vavalà, Tiziana; Whiteley, Andrew R.; Chen, Heidi; Yan, Yingjun; Sheehan, Jonathan H.; Meiler, Jens; Morosini, Deborah; Ross, Jeffrey S.; Stephens, Philip J.; Miller, Vincent A.; Ali, Siraj M.; Lovly, Christine M.

doi:10.1158/2159-8290.cd-16-0075

Cited by 111 publications

(137 citation statements)

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“…Eloquent structural and biochemical experiments have irrefutably defined that the addition of EGFR-T790M to a sensitizing mutant alters the kinetics of inhibitor binding of gefitinib, erlotinib and afatinib (29,30); leading to resistance to achievable clinical doses of these EGFR TKIs. However, 3 rd generation EGFR TKIs that were selected on the basis of their covalent binding to EGFR-C797, plus their mutation over WT EGFR sensitivity, can inhibit EGFR-T790M bearing cancers (6,31 and EGFR rearrangements (34,35). It seems the frequency of these changes does not exceed individually 0.5% of all EGFR mutation events ( Table 1).…”

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confidence: 99%

“…It seems the frequency of these changes does not exceed individually 0.5% of all EGFR mutation events ( Table 1). In the 1,510 EGFR mutated tumor cohort described from 10,097 analyzed cases using FoundationOne's comprehensive genomic profiling (35), the frequency of EGFR-KDD was 0.2% and of EGFR rearrangements was 0.3% ( Figure 1). These changes had not been reported previously because most traditional EGFR sequencing strategies used in day-to-day clinical care (Sanger sequencing, allele-specific PCR-based or focused next generation sequencing panels) are unable to identify these rare genomic variants.…”

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confidence: 99%

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“…The two reported partners include the C-terminal portion of the RAD51 recombinase (RAD51) or purine-rich element binding protein B (PURB) genes (35). The resulting N-terminal EGFR-RAD51 C-terminal fusion protein retains an important regulatory auto-phosphorylation site (Y845) of EGFR (35). In preclinical models, EGFR-RAD51 is transforming, activates downstream signaling pathways, may form activation dimers, and is hypersensitive to 1 st , 2 nd and 3 rd generation EGFR TKIs (35).…”

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confidence: 99%

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Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

Costa¹

2016

Transl. Lung Cancer Res.

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Epidermal growth factor receptor (EGFR) mutations were first identified as driver oncogenes in non-small-cell lung cancers (NSCLCs) in 2004 by three separate independent groups (1-3), and originally thought to consistent of only inframe deletions, insertions (i.e., indels) or point mutations within exons 18 to 21 of the kinase domain of EGFR (4). The most abundant EGFR mutations are deletions/indels (around amino-acid residues 747 to 752) of exon 19 (these account for ~45% of all EGFR mutations, with the most common delE746_A750) and the exon 21 point mutation L858R mutation (~35% of all EGFR mutations). Inhibition of mutant EGFR in preclinical models through tyrosine kinase inhibitors (TKIs) unsettles the intracellular signaling cascade, generating cell cycle arrest and apoptosis (5). In the clinic, the 1 st generation EGFR TKIs gefitinib and erlotinib, both reversible ATP mimetics with a favorable therapeutic window in relation to the wild-type (WT) EGFR (4,6), induce overall response rate (ORR), EditorialKinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements that comprehensive molecular profiling may be necessary to maximize the identification of all cases that can benefit from precision oncology.

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confidence: 99%

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confidence: 99%

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Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

Costa¹

2016

Transl. Lung Cancer Res.

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“…As reported, assessing the mutation of EGFR [33] and the other genes were the accepted standard of care worldwide for patients with lung cancer.…”

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Early Diagnosis with 11-Gene Panel Screening for Non Small Cell Lung Cancer

Gao¹

2017

IJCAM

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Actionable Structural Variant Detection via RNA-NGS and DNA-NGS in Patients With Advanced Non–Small Cell Lung Cancer

Owen,

Ben-Shachar,

Feliciano

et al. 2024

JAMA Netw Open

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ImportanceThe National Comprehensive Cancer Network (NCCN) guidelines for non–small cell lung cancer suggest that RNA next-generation sequencing (NGS) may improve the detection of fusions and splicing variants compared with DNA-NGS alone. However, there is limited adoption of RNA-NGS in routine oncology clinical care today.ObjectiveTo analyze clinical evidence from a diverse cohort of patients with advanced lung adenocarcinoma and compare the detection of NCCN-recommended actionable structural variants (aSVs; fusions and splicing variants) via concurrent DNA and RNA-NGS vs DNA-NGS alone.Design, Setting, and ParticipantsThis multisite, retrospective cohort study examined patients sequenced between February 2021 and October 2023 within the deidentified, Tempus multimodal database, consisting of linked molecular and clinical data. Participants included patients with advanced lung adenocarcinoma and sufficient tissue sample quantities for both RNA-NGS and DNA-NGS testing.ExposuresReceived results from RNA-NGS and DNA-NGS solid-tissue profiling assays.Main Outcomes and MeasuresDetection rates of NCCN guideline–based structural variants (ALK, ROS1, RET and NTRK1/2/3 fusions, as well as MET exon 14 skipping splicing alterations) found uniquely by RNA-NGS.ResultsIn the evaluable cohort of 5570 patients, median (IQR) age was 67.8 (61.3-75.4) years, and 2989 patients (53.7%) were female. The prevalence of actionable structural variants detected by either RNA-NGS or DNA-NGS was 8.8% (n = 491), with 86.7% (n = 426) of these detected by DNA-NGS. Concurrent RNA-NGS and DNA-NGS identified 15.3% more patients harboring aSVs compared with DNA-NGS alone (491 vs 426 patients, respectively), including 14.3% more patients harboring actionable fusions (376 vs 329 patients) and 18.6% more patients harboring MET exon 14 skipping alterations (115 vs 97 patients). There was no significant association between the assay used for aSV detection and aSV-targeted therapeutic adoption or clinical outcome. Emerging structural variants (eSVs) were found to have a combined prevalence to be 0.7%, with only 47.5% of eSVs detected by DNA-NGS.Conclusions and RelevanceIn this cohort study, the detection of structural variants via concurrent RNA-NGS and DNA-NGS was higher across multiple NCCN-guideline recommended biomarkers compared with DNA-NGS alone, suggesting that RNA-NGS should be routinely implemented in the care of patients with advanced NSCLC.

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EGFR Fusions as Novel Therapeutic Targets in Lung Cancer

Cited by 111 publications

References 31 publications

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

Kinase inhibitor-responsive genotypes in EGFR mutated lung adenocarcinomas: moving past common point mutations or indels into uncommon kinase domain duplications and rearrangements

Early Diagnosis with 11-Gene Panel Screening for Non Small Cell Lung Cancer

Actionable Structural Variant Detection via RNA-NGS and DNA-NGS in Patients With Advanced Non–Small Cell Lung Cancer

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