Incidence of ERBB gene fusions (EGFR, ERBB2, ERBB4) across tumor types.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3091-3091
Author(s):  
Laura Schubert ◽  
Andrew Elliott ◽  
Robert Charles Doebele ◽  
Emil Lou ◽  
Hossein Borghaei ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Gastroesophageal Junction ◽  
Functional Characterization ◽  
Kinase Domain ◽  
Data Sets ◽  
Gene Fusions ◽  
Cancer Subtypes ◽  
Multiple Tumor ◽  
Public Data ◽  
Tumor Types

3091 Background: Gene fusions often represent critical therapeutic targets across cancer subtypes. Fusions within the ErbB family of receptor tyrosine kinases, including EGFR, ERBB2 ( HER2) and ERBB4 ( HER4), have been previously described and represent potentially actionable alterations. Here, we report the relative incidence and functional characterization of these rare genomic events. Methods: Tumor samples (n = 64,354; representing > 40 tumors types) submitted to Caris Life Sciences (Phoenix, AZ) were molecularly profiled by next-generation sequencing of DNA (NextSeq, 592-gene panel; or NovaSeq, whole exome) and RNA (whole transcriptome). Gene fusion partners, in/out-of-frame status, retention of ERBB kinase domain, and topology of fusion breakpoints were characterized for each ERBB fusion transcript detected. Fusion prevalence was further examined in public data sets (TCGA, MSK-IMPACT and AACR GENIE). Results: From the Caris database, a total of 64 EGFR fusion isoforms were detected in 59 tumors (incidence 0.09%); 83% were in-frame and 91% retained the EGFR kinase domain. 206 ERBB2 fusion isoforms were detected in 114 tumors (0.18%); 37% were in-frame and 34% retained the ERBB2 kinase domain. 131 ERBB4 fusion isoforms were detected in 108 tumors (0.17%); 62% were in-frame and 51% retained the kinase domain. All fusions were detected at low incidence across all tumor types. EGFR fusions were most common in high grade glioma (1.7%, n = 35), largely driven by recurrent EGFR-SEPT14 fusions (n = 20). ERBB2 fusions were most common in esophageal/gastroesophageal junction carcinoma (1.1%, n = 20), with recurrent fusion to PGAP3 observed in multiple tumor types (n = 37). ERBB4 fusions were most common in ovarian (0.7%, n = 40) and bladder (0.7%, n = 15) cancers, which often resulted from recurrent fusion with IKZF2 (n = 36). EGFR and ERBB2 fusions were generated predominantly (44-48%) from inversion events, while ERBB4 fusions arose more frequently and at similar rates (27-32%) from deletions, duplications, or translocations. Mining of public data sets corroborated the prevalence of ERBB gene fusions: the frequency of EGFR fusions was 0.63%, ERBB2 was 0.14% and ERBB4 was 0.04%. TP53 mutations frequently co-occurred with ERBB2 and ERBB4 fusions ( > 60% average across public data sets), with higher co-mutation rates ( > 70%) observed for samples in the Caris database. Conclusions: ERBB gene fusions are detectable at low frequency in various tumor types and may represent a unique genomic subset of cancer. Identification of novel ERBB gene fusions warrants further investigation to determine the potential pathogenicity and actionability of these fusions.

scholarly journals Therapeutic strategies in RET gene rearranged non-small cell lung cancer

2021 ◽  
Vol 14 (1) ◽  
Author(s):  
Leylah M. Drusbosky ◽  
Estelamari Rodriguez ◽  
Richa Dawar ◽  
Chukwuemeka V. Ikpeazu
Keyword(s):  
Acquired Resistance ◽  
Kinase Domain ◽  
Significant Activity ◽  
Gene Fusions ◽  
Multiple Tumor ◽  
Ret Gene ◽  
Clinical Benefits ◽  
Nsclc Patients ◽  
Tumor Types

AbstractThe recent approvals by the Food and Drug Administration several tumor-agnostic drugs have resulted in a paradigm shift in cancer treatment from an organ/histology-specific strategy to biomarker-guided approaches. RET gene fusions are oncogenic drivers in multiple tumor types and are known to occur in 1–2% of non-squamous NSCLC patients. RET gene fusions give rise to chimeric, cytosolic proteins with constitutively active RET kinase domain. Standard therapeutic regimens provide limited benefit for NSCLC patients with RET fusion-positive tumors, and the outcomes with immunotherapy in the these patients are generally poor. Selpercatinib (LOXO-292) and pralsetinib (BLU-667) are potent and selective inhibitors that target RET alterations, including fusions and mutations, irrespective of the tissue of origin. Recently, the results from the LIBRETTO-001 and ARROW clinical trials demonstrated significant clinical benefits with selpercatinib and pralsetinib respectively, in NSCLC patients with RET gene fusions, with tolerable toxicity profiles. These studies also demonstrated that these RET-TKIs crossed the blood brain barrier with significant activity. As has been observed with other TKIs, the emergence of acquired resistance may limit long-term efficacy of these agents. Therefore, understanding the mechanisms of resistance is necessary for the development of strategies to overcome them.

Acral Lentiginous Melanoma Harboring a ROS1 Gene Fusion With Clinical Response to Entrectinib

2017 ◽  
pp. 1-7 ◽  
Author(s):  
Kasey L. Couts ◽  
Caroline E. McCoach ◽  
Danielle Murphy ◽  
Jason Christiansen ◽  
Jacqueline Turner ◽  
...  
Keyword(s):  
Clinical Response ◽  
Cutaneous Melanoma ◽  
Gene Fusions ◽  
Small Cell Lung ◽  
Durable Response ◽  
Acral Lentiginous Melanoma ◽  
Multiple Tumor ◽  
Alk Inhibitor ◽  
Basket Trial ◽  
Tumor Types

Purpose ROS1 gene fusions demonstrate oncogenic activity, and patients with non–small-cell lung cancer (NSCLC) harboring a ROS1 fusion benefit from the use of a ROS1 inhibitor; however, clinical response to ROS1 inhibitors remains largely uncharacterized outside of NSCLC. ROS1 fusions have been identified in multiple tumor types but have not been reported in cutaneous melanoma. Patients and Methods Tumors from 22 patients with acral lentiginous melanoma (ALM) were analyzed with targeted RNA sequencing to detect fusions in ROS1, NTRK1, NTRK2, NTRK3, and ALK genes. A patient harboring a ROS1 fusion was enrolled in a phase I basket trial of a ROS1/TRK/ALK inhibitor (entrectinib). An additional 78 tumors with different subtypes of melanoma were screened by ROS1 immunohistochemistry. Results Targeted sequencing identified a GOPC- ROS1 fusion in a patient with ALM. The patient underwent a dramatic and durable response to entrectinib, with a RECIST (version 1.1) partial response of −38% at 3 months and −55% at 11 months. The response is ongoing, and the patient has not developed any new lesions. No additional ROS1 fusions were identified by immunohistochemistry, resulting in a frequency of 3.0% in ALM and 1.3% in all melanomas. Conclusion ROS1 fusions occur and can respond to targeted therapy in cutaneous melanoma; however, they may be specific to ALM subtype. This report expands knowledge of ROS1 inhibitor response outside of NSCLC and identifies new therapeutic options for a subset of patients with ALM.

scholarly journals Introduction to DOK2 and its Potential Role in Cancer

2021 ◽  
pp. 671-685
Author(s):  
P SUN ◽  
R LI ◽  
Y MENG ◽  
S XI ◽  
Q WANG ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Potential Role ◽  
Suppressor Gene ◽  
Modern Medicine ◽  
Mechanisms Of Action ◽  
Multiple Tumor ◽  
Tyrosine Kinase 2 ◽  
Prevention And Treatment ◽  
Tumor Types

Cancer is a complex, multifactorial disease that modern medicine ultimately aims to overcome. Downstream of tyrosine kinase 2 (DOK2) is a well-known tumor suppressor gene, and a member of the downstream protein DOK family of tyrosine kinases. Through a search of original literature indexed in PubMed and other databases, the present review aims to extricate the mechanisms by which DOK2 acts on cancer, thereby identifying more reliable and effective therapeutic targets to promote enhanced methods of cancer prevention and treatment. The review focuses on the role of DOK2 in multiple tumor types in the lungs, intestines, liver, and breast. Additionally, we discuss the potential mechanisms of action of DOK2 and the downstream consequences via the Ras/MPAK/ERK or PI3K/AKT/mTOR signaling pathways.

scholarly journals OR28-04 Identification of Novel and Rare Receptor Tyrosine Kinase Fusions in Thyroid Fine Needle Aspirates

2020 ◽  
Vol 4 (Supplement_1) ◽  
Author(s):  
Lori J Wirth ◽  
Elizabeth G Grubbs ◽  
Masha J Livhits ◽  
Steven I Sherman ◽  
Steven P Weitzman ◽  
...  
Keyword(s):  
Tyrosine Kinases ◽  
Kinase Inhibitors ◽  
Chromosomal Rearrangements ◽  
Kinase Domain ◽  
Fusion Partner ◽  
Gene Fusions ◽  
Rna Seq ◽  
Fine Needle Aspirates ◽  
Genomic Markers ◽  
Treatment Naïve

Abstract Introduction: Receptor tyrosine kinases (RTKs) initiate signaling cascades, including growth and differentiation. Activation can occur through chromosomal rearrangements that lead to gene fusions. RTK fusions are potential targets for small molecule inhibitors to treat advanced cancers. The original Afirma Xpression Atlas (XA) reported 761 selected variants and 130 fusion pairs in Bethesda III/IV Afirma Genomic Sequencing Classifier (GSC) suspicious or Bethesda V/VI nodules. The landscape of additional potentially actionable gene fusions has not been explored in treatment-naïve patients. Methods: Anonymized RNA-seq data from >37,000 Bethesda III-VI samples were examined with STAR-fusion to determine gene/gene fusions. All samples were examined for NTRK1, NTRK3, RET, ALK, and BRAF fusions, regardless of fusion partner. Fusions were evaluated for being in-frame, with an intact kinase domain at the 3’ end of the fusion pair. Fusion pairs not currently reported by XA and not reported in thyroid TCGA fusion data are denoted “additional”. All fusion pairs were searched for in the literature and public fusion databases. Results: Examining the Veracyte clinical database revealed 7 additional NTRK1/3 fusions, with 3 NTRK fusions observed more than once - SQSTM1/NTRK3, VIM/NTRK3, and EML4/NTRK3. One of the 7 NTRK fusions had not been previously reported. Eight additional ALK fusions were identified, with 4 observed more than once- ITSN2/ALK, PPP1R21/ALK, PDE8B/ALK, NPAT/ALK. Five of these 8 ALK fusions had not been previously described. Seventeen additional RET fusions were identified, with 5 observed recurrently - KIAA1217/RET, AFAP1L2/RET, ACBD5/RET, SQSTM1/RET, and TFG/RET. Six of the 17 RET fusions had not been previously reported. Seventy-two additional BRAF fusions were identified, and 58 of them have not been previously reported. Eight of the 72 BRAF fusions were observed more than once. Examining >50,000 Afirma samples, NTRK1, NTRK3, RET, ALK, or BRAF fusions were not identified among the Afirma GSC Benign, and were present in 3.2% of 16,594 Bethesda III/IV Afirma GSC Suspicious samples, and 8.0% of 1,692 Bethesda V/VI samples. Correlation with surgical histology is unknown. Conclusions: By examining a large cohort of patients with an unbiased, whole-transcriptome RNA-seq assay, we identified potentially actionable kinase fusions in thyroid nodules beyond those described in TCGA. All fusions described here are either novel and not previously reported, rarely reported in one or two case studies, or not described in thyroid cancers. Additional NTRK, ALK, RET and BRAF fusions were found, all of which may be targeted with specific kinase inhibitors currently available. Future studies may determine genotype-phenotype correlations regarding the natural history of these neoplasms. Because of the potential clinical implications of these genomic markers for patient management, all 104 fusions described here are now included among the 235 gene pairs reported by the expanded Afirma XA.

scholarly journals Arabidopsis Transmembrane Receptor-Like Kinases (RLKs): A Bridge between Extracellular Signal and Intracellular Regulatory Machinery

2020 ◽  
Vol 21 (11) ◽  
pp. 4000 ◽  
Author(s):  
Jismon Jose ◽  
Swathi Ghantasala ◽  
Swarup Roy Choudhury
Keyword(s):  
Ligand Binding ◽  
Stress Responses ◽  
Tyrosine Kinases ◽  
Functional Characterization ◽  
Kinase Domain ◽  
Amino Terminal ◽  
Binding Domains ◽  
Regulatory Machinery ◽  
Considerable Homology ◽  
Membrane Spanning

Receptors form the crux for any biochemical signaling. Receptor-like kinases (RLKs) are conserved protein kinases in eukaryotes that establish signaling circuits to transduce information from outer plant cell membrane to the nucleus of plant cells, eventually activating processes directing growth, development, stress responses, and disease resistance. Plant RLKs share considerable homology with the receptor tyrosine kinases (RTKs) of the animal system, differing at the site of phosphorylation. Typically, RLKs have a membrane-localization signal in the amino-terminal, followed by an extracellular ligand-binding domain, a solitary membrane-spanning domain, and a cytoplasmic kinase domain. The functional characterization of ligand-binding domains of the various RLKs has demonstrated their essential role in the perception of extracellular stimuli, while its cytosolic kinase domain is usually confined to the phosphorylation of their substrates to control downstream regulatory machinery. Identification of the several ligands of RLKs, as well as a few of its immediate substrates have predominantly contributed to a better understanding of the fundamental signaling mechanisms. In the model plant Arabidopsis, several studies have indicated that multiple RLKs are involved in modulating various types of physiological roles via diverse signaling routes. Here, we summarize recent advances and provide an updated overview of transmembrane RLKs in Arabidopsis.

Clinicopathologic features of non-small cell lung cancer (NSCLC) harboring an NTRK gene fusion.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11580-11580 ◽  
Author(s):  
Anna F. Farago ◽  
Martin S Taylor ◽  
Robert Charles Doebele ◽  
Alexander I. Spira ◽  
Theresa A Boyle ◽  
...  
Keyword(s):  
Kinase Domain ◽  
Smoking History ◽  
Study Cohort ◽  
Gene Fusions ◽  
Clinicopathologic Features ◽  
Oncogenic Driver ◽  
Specific Position ◽  
Trk Inhibitors ◽  
Tumor Types ◽  
Next Generation Sequencing Ngs

11580 Background: Gene fusions involving NTRK1/2/3 can generate oncoproteins containing the kinase domains of TRKA/B/C, respectively. Inhibition of TRK signaling has led to dramatic responses across tumor types with NTRK fusions. An estimated 0.1 – 1% of NSCLCs harbor NTRK fusions. To date, clinical and radiographic responses to TRK inhibitors have been reported for 2 NTRK fusion-positive NSCLCs (Farago et al., 2015; Hong et al., 2016). Despite the potential benefit of identifying these fusions, the clinicopathologic features of NTRK fusion NSCLCs are not well characterized. Methods: Physicians across multiple institutions contributed deidentified cases to an NTRK fusion NSCLC database. A central pathologist (M.M.) reviewed tumor histology in cases with available tissue. Results: 10 NSCLC cases with NTRK gene fusions were identified. Of these, TRK kinase domain-containing potentially activating fusions were verified by next-generation sequencing (NGS) in 7, forming the study cohort. Fusions involved NTRK1 (6) and NTRK3 (1) with 6 different partners. Four (57%) patients were male. Median age at diagnosis was 47.6 years (range 27.9 – 86.0). The average smoking pack year history was 8.9 (range 0 to 30). Five (71%) presented with metastatic disease. No concurrent alterations in KRAS, EGFR, ALK, ROS1, or other known drivers were identified in the study cohort cases. On pathologic review of 4 cases, all were adenocarcinoma, including 2 invasive mucinous adenocarcinomas and 1 adenocarcinoma with neuroendocrine features. Of the 3 remaining non-study cohort cases, 1 was a non-kinase domain-containing NTRK1 fusion with a concurrent KRAS G12C mutation, 1 was an NTRK2 intragenic deletion disrupting the exon 18 3’ splice site, and 1 was an NTRK1 alteration detected by FISH but not verified by NGS and with a concurrent HER2 L755P mutation. Conclusions: NTRK fusions occur in both men and women across wide ranges in age and smoking history. We therefore suggest that all NSCLC adenocarcinomas without other oncogenic driver alterations be screened for NTRK fusions. Notably, not all NTRK alterations are activating, requiring validation of the specific position of the fusion.

scholarly journals Deep computational analysis of human cancer and non-cancer tissues details dysregulation of eIF4F components and their interactions in human cancers

2020 ◽  
Author(s):  
Su Wu ◽  
Gerhard Wagner
Keyword(s):  
Translation Initiation ◽  
Human Cancer ◽  
Data Sets ◽  
Eukaryotic Translation ◽  
Human Cancers ◽  
Gene Copies ◽  
Public Data ◽  
Eukaryotic Translation Initiation ◽  
Tumor Types ◽  
Cancer Tissues

SUMMARYEukaryotic translation initiation complex (eIF4F) plays roles so diverse in human cancers as to complicate development of an overarching understanding of eIF4F’s functional and regulatory impacts across tumor types. Our analysis of large public data sets yielded several useful findings. EIF4G1 frequently gains gene copies and is overexpressed to achieve characteristic stoichiometries with EIF4E and EIF4A1 in cancers. Varied expressions among EIF4F components distinguish malignant from healthy tissues, regardless of tissue or cancer types. EIF4G1 expression in particular correlates with poor prognosis. Tumors dysregulate biological “house-keeping” pathways typically regulated by cap-dependent initiation in healthy tissues, yet strengthen regulation of cancer-specific pathways in cap-independent contexts. In lung adenocarcinoma, altered interactions among eIF4F subunits are mechanistically linked to eIF4G1 phosphorylation. Tumors may select between cap-dependent and -independent mechanisms, through eIF4G1’s adaptable interactions with eIF4F subunits. Collectively, these results are an important advance towards a general model of translation initiation in cancer.

scholarly journals A phospho-switch in the N-terminus of NRT2.1 affects nitrate uptake by controlling the interaction of NRT2.1 with NAR2.1

2020 ◽  
Author(s):  
Zhi Li ◽  
Xu Na Wu ◽  
Aurore Jaquot ◽  
Larence Lejay ◽  
Waltraud X Schulze
Keyword(s):  
Nitrate Uptake ◽  
Functional Characterization ◽  
Kinase Domain ◽  
Data Sets ◽  
C Terminus ◽  
N Terminus ◽  
Switch Mechanism ◽  
A Site ◽  
Nitrate Starvation

AbstractNRT2.1 can be phosphorylated at five different sites within N- and C-terminus. Here, we provide a systematic functional characterization of phosphorylation at S21 and S28 within the N-terminus of NRT2.1. We used existing phosphoproteomic data sets of nitrate starvation and nitrate resupply to construct a site-specific correlation network identifying kinase candidates to phosphorylate NRT2.1. By this approach, we identified NITRATE UPTAKE REGULATORY KINASE 1 (AT5G49770) which itself was regulated by phosphorylation at S839 and S870 within its kinase domain. In the active state, when S839 was dephosphorylated and S870 was phosphorylated, NURK1 was found to interact with NRT2.1 at dephosphorylated S28. Upon that interaction, NURK1 can phosphorylate NRT2.1 at S21. Phosphorylation of NRT2.1 at S21 resulted in low interaction of NRT2.1 with its activator protein NAR2.1. By contrast, phosphorylation of NRT2.1 at S28 by a yet unknown kinase enhanced the interaction with NAR2.1, but inhibited the interaction with NURK1. We propose that serines S21 and S28 are involved in a phospho-switch mechanism and by which the interaction of NRT2.1 with its activator NAR2.1, and thus NRT2.1 activity, is modulated. NURK1 here was identified as the kinase affecting this phospho-switch through phosphorylation of NRT2.1 at S21 leading to inactivation of NRT2.1.

scholarly journals Elucidation of a four-site allosteric network in fibroblast growth factor receptor tyrosine kinases

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Huaibin Chen ◽  
William M Marsiglia ◽  
Min-Kyu Cho ◽  
Zhifeng Huang ◽  
Jingjing Deng ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinases ◽  
Functional Characterization ◽  
Growth Factor Receptor ◽  
Structural Similarity ◽  
Kinase Domain ◽  
Tyrosine Kinase Domain ◽  
Active Conformation ◽  
Long Distance ◽  
Fgf Receptor

Receptor tyrosine kinase (RTK) signaling is tightly regulated by protein allostery within the intracellular tyrosine kinase domains. Yet the molecular determinants of allosteric connectivity in tyrosine kinase domain are incompletely understood. By means of structural (X-ray and NMR) and functional characterization of pathogenic gain-of-function mutations affecting the FGF receptor (FGFR) tyrosine kinase domain, we elucidated a long-distance allosteric network composed of four interconnected sites termed the ‘molecular brake’, ‘DFG latch’, ‘A-loop plug’, and ‘αC tether’. The first three sites repress the kinase from adopting an active conformation, whereas the αC tether promotes the active conformation. The skewed design of this four-site allosteric network imposes tight autoinhibition and accounts for the incomplete mimicry of the activated conformation by pathogenic mutations targeting a single site. Based on the structural similarity shared among RTKs, we propose that this allosteric model for FGFR kinases is applicable to other RTKs.

scholarly journals Targeting AURKA in Cancer: molecular mechanisms and opportunities for Cancer therapy

2021 ◽  
Vol 20 (1) ◽  
Author(s):  
Ruijuan Du ◽  
Chuntian Huang ◽  
Kangdong Liu ◽  
Xiang Li ◽  
Zigang Dong
Keyword(s):  
Cancer Therapy ◽  
Molecular Mechanisms ◽  
Aurora Kinase ◽  
Interacting Proteins ◽  
Multiple Tumor ◽  
Oncogenic Pathways ◽  
Wide Range ◽  
The Family ◽  
Tumor Types ◽  
Cancer Tissues

AbstractAurora kinase A (AURKA) belongs to the family of serine/threonine kinases, whose activation is necessary for cell division processes via regulation of mitosis. AURKA shows significantly higher expression in cancer tissues than in normal control tissues for multiple tumor types according to the TCGA database. Activation of AURKA has been demonstrated to play an important role in a wide range of cancers, and numerous AURKA substrates have been identified. AURKA-mediated phosphorylation can regulate the functions of AURKA substrates, some of which are mitosis regulators, tumor suppressors or oncogenes. In addition, enrichment of AURKA-interacting proteins with KEGG pathway and GO analysis have demonstrated that these proteins are involved in classic oncogenic pathways. All of this evidence favors the idea of AURKA as a target for cancer therapy, and some small molecules targeting AURKA have been discovered. These AURKA inhibitors (AKIs) have been tested in preclinical studies, and some of them have been subjected to clinical trials as monotherapies or in combination with classic chemotherapy or other targeted therapies.

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