<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 103 publications

(125 citation statements)

References 31 publications

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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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confidence: 99%

“…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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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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Next‐Generation Kinase Inhibitors Targeting Specific Biomarkers in Non‐Small Cell Lung Cancer (NSCLC): A Recent Overview

2021

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Lung cancer causes many deaths globally. Mutations in regulatory genes, irregularities in specific signal transduction events, or alterations of signalling pathways are observed in cases of non‐small cell lung cancer (NSCLC). Over the past two decades, a few kinases have been identified, validated, and studied as biomarkers for NSCLC. Among them, EGFR, ALK, ROS1, MET, RET, NTRK, and BRAF are regarded as targetable biomarkers to cure and/or control the disease. In recent years, the US Food and Drug Administration (FDA) approved more than 15 kinase inhibitors targeting these NSCLC biomarkers. The kinase inhibitors significantly improved the progression‐free survival (PFS) of NSCLC patients. Challenges still remain for metastatic diseases and advanced NSCLC cases. New discoveries of potent kinase inhibitors and rapid development of modern medical technologies will help to control NSCLC cases. This article provides an overview of the discoveries of various types of kinase inhibitors against NSCLC, along with medicinal chemistry aspects and related developments in next‐generation kinase inhibitors that have been reported in recent years.

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EGFR Fusions as Novel Therapeutic Targets in Lung Cancer

Cited by 103 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

Next‐Generation Kinase Inhibitors Targeting Specific Biomarkers in Non‐Small Cell Lung Cancer (NSCLC): A Recent Overview

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