Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations

Pahuja, Kanika Bajaj; Nguyen, Thong Tien; Jaiswal, Bijay S.; Prabhash, Kumar; Thaker, Tarjani; Senger, Kate; Chaudhuri, Subhra; Kljavin, Noelyn M.; Antony, Aju; Phalke, Sameer; Kumar, Prasanna; Mravic, Marco; Stawiski, Eric; Vargas, Derek; Durinck, Steffen; Gupta, Ravi; Khanna-Gupta, Arati; Trabucco, Sally E.; Sokol, Ethan S.; Hartmaier, Ryan J.; Singh, Ashish; Chougule, Anuradha; Trivedi, Vaishakhi; Dutt, Amit; Patil, Vijay; Joshi, Amit; Noronha, Vanita; Ziai, James; Banavali, Sripad; Ramprasad, Vedam; DeGrado, William F.; Bueno, Raphael; Jura, Natalia; Seshagiri, Somasekar

doi:10.1016/j.ccell.2018.09.010

Cited by 122 publications

(134 citation statements)

References 79 publications

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“…To assess the therapeutic implications of molecular events in our set of variants, we used Database of Evidence for Precision Oncology (DEPO; http://depo-dinglab.ddns.net) that focuses on specific mutations (STAR Methods) and casts therapeutic projections based on FDA-approved therapies, clinical trials, and published clinical evidence [28]. Of note, 2 variants in the PDGFRA gene (p.[Arg817Cys] in exon 18 and p.[Leu660Phe] in exon 14) found in MM were already described as a target of imatinib and an FDA-approved targeted therapy for GIST patients.…”

Section: Resultsmentioning

confidence: 99%

“…Recently, a TCGA cohort comprising 74 tumors revealed 13.5% of TP53 mutations [16]. Hmeljak et al [16] showed that TP53 is one of the MPM driver genes, together with BAP1, SETD2 , and NF2 , and is associated with aggressive behavior [16, 28]. They showed 13 TP53 mutations, mainly SNV type, missense type, and in exons 5–8 (all these alterations were found in 10/13 mutated cases), as found by us, but in different nucleotides [16].…”

Section: Discussion/conclusionmentioning

confidence: 99%

“…Additionally, by targeted NGS, we found 18.2% of cases with at least 1 variant in the ERBB2 gene. Despite ERBB2 mutations occurring in multiple cancers [28], this is the first report in MPM. ERBB2 is a member of the human epidermal growth factor receptor (HER) family of receptor tyrosine kinases, of which overexpression results in the oncogenic transformation of cells [35].…”

Section: Discussion/conclusionmentioning

confidence: 99%

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Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas

et al. 2020

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Background: Malignant pleural mesothelioma (MPM) is a highly lethal disease comprising a heterogeneous group of tumors with challenging to predict biological behavior. The diagnosis is complex, and the histologic classification includes 2 major subtypes of MPM: epithelioid (∼60% of cases) and sarcomatous (∼20%). Its identification depends upon pathological investigation supported by clinical and radiological evidence and more recently ancillary molecular testing. Treatment options are currently limited, with no known targeted therapies available. Objectives: To elucidate the mutation profile of driver tumor suppressor and oncogenic genes in a cohort of Brazilian patients. Methods: We sequenced 16 driver genes in a series of 43 Brazilian malignant mesothelioma (MM) patients from 3 distinct Brazilian centers. Genomic DNA was extracted from formalin-fixed paraffin-embedded tumor tissue blocks, and the TERT promoter region was amplified by PCR followed by direct capillary sequencing. The Illumina TruSight Tumor 15 was used to evaluate 250 amplicons from 15 genes associated with solid tumors (AKT1, GNA11, NRAS, BRAF, GNAQ, PDGFRA, EGFR, KIT, PIK3CA, ERBB2, KRAS, RET, FOXL2, MET,and TP53). Library preparation with the TruSight Tumor 15 was performed before sequencing at the MiSeq platform. Data analysis was performed using Sophia DDM software. Results: Out of 43 MPM patients, 38 (88.4%) were epithelioid subtype and 5 (11.6%) were sarcomatoid histotype. Asbestos exposure was present in 15 (39.5%) patients with epithelioid MPM and 3 (60%) patients with sarcomatoid MPM. We found a TERT promoter mutation in 11.6% of MM, and the c.-146C>T mutation was the most common event. The next-generation sequencing was successful in 33 cases. A total of 18 samples showed at least 1 pathogenic, with a median of 1.8 variants, ranging from 1 to 6. The most mutated genes were TP53 and ERBB2 with 7 variants each, followed by NRAS BRAF, PI3KCA, EGFR and PDGFRA with 2 variants each. KIT, AKT1, and FOXL2 genes exhibited 1 variant each. Interestingly, 2 variants observed in the PDGFRA gene are classic imatinib-sensitive therapy. Conclusions: We concluded that Brazilian MPM harbor mutation in classic tumor suppressor and oncogenic genes, which might help in the guidance of personalized treatment of MPM.

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Section: Resultsmentioning

confidence: 99%

Section: Discussion/conclusionmentioning

confidence: 99%

Section: Discussion/conclusionmentioning

confidence: 99%

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Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas

et al. 2020

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“…Mutations or deletions in EGFR and HER2 result in ligand-independent receptor activation, indicating that in addition to being activated in the presence of ligand, ERBBs are actively inhibited in the absence of ligand (25)(26)(27)(28)(29)(30). The mechanism for this autoinhibition remains incompletely understood, however.…”

Section: Introductionmentioning

confidence: 99%

Ligand-independent EGFR oligomers do not rely on the active state asymmetric kinase dimer

Byrne

Hristova²,

Leahy

2020

Preprint

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The human Epidermal Growth Factor Receptor (EGFR/ERBB1) is a Receptor Tyrosine Kinase (RTK) that forms active oligomers in response to ligand. Much evidence indicates that EGFR/ERBB1 forms oligomers in the absence of ligand, but the structure and physiological role of these ligandindependent dimers remain unclear. We use fluorescence microscopy to measure the oligomer stability and FRET efficiency for homo-and hetero-oligomers of fluorescent-protein labeled forms of EGFR and its paralog, Human Epidermal Growth Factor Receptor 2 (HER2/ERBB2) in vesicles derived from native cell membranes. Both receptors form ligand-independent oligomers at physiological plasma membrane concentrations. Mutations introduced in the EGFR kinase region at a key interface within the active state dimer alter the FRET efficiency within ligand-independent EGFR oligomers but do not affect their stability. These results indicate that ligand-independent EGFR oligomers do not require this interface and that the inactive state ensemble is distinct from the EGFR active state ensemble.

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“…ERBB2 (HER2) mutations have emerged as a novel biomarker and occur by the majority in patients without HER2 amplification [2], but also in HER2-amplified cases [53]. Evidence is mounting that recurrent ERBB2 mutations lead to increased activation of the HER2 receptor in tumors classified as HER2-normal [2,51,95]. Activating ERBB2 mutations have been shown to confer therapy resistance against standard of care drugs such as trastuzumab and lapatinib [53], but can be overcome using pan-HER tyrosine kinase inhibitors such as neratinib [2,96,97,53].…”

Section: Discussionmentioning

confidence: 99%

The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

Brueffer

Gladchuk

Winter

et al. 2020

Preprint

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Breast cancer is a disease of genomic alterations, of which the complete panorama of somatic mutations and how these relate to molecular subtypes and therapy response is incompletely understood. Within the Sweden Cancerome Analysis Network-Breast project (SCAN-B; ClinicalTrials.gov NCT02306096), an ongoing study elucidating the tumor transcriptomic profiles for thousands of breast cancers prospectively, we developed an optimized pipeline for detection of single nucleotide variants and small insertions and deletions from RNA sequencing (RNA-seq) data, and profiled a large real-world population-based cohort of 3,217 breast tumors. We use it to describe the mutational landscape of primary breast cancer viewed through the transcriptome of a large population-based cohort of patients, and relate it to patient overall survival. We demonstrate that RNA-seq can be used to call mutations in important breast cancer genes such as PIK3CA, TP53, and ERBB2, as well as the status of key molecular pathways and tumor mutational burden, and identify potentially druggable genes in 86.8% percent of tumors. To make this rich and growing mutational portraiture of breast cancer available for the wider research community, we developed an open source web-based application, the SCAN-B MutationExplorer, accessible at http://oncogenomics.bmc.lu.se/MutationExplorer. These results add another dimension to the use of RNA-seq as a potential clinical tool, where both gene expression-based and gene mutation-based biomarkers can be interrogated simultaneously and in real-time within one week of tumor sampling. and sampling of tissue for this study. We also thank the Swedish National Breast Cancer Registry and Regional Cancer Center South for clinical data. The SweGen allele frequency data was generated

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Actionable Activating Oncogenic ERBB2/HER2 Transmembrane and Juxtamembrane Domain Mutations

Cited by 122 publications

References 79 publications

Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas

Mutational Profiling of Driver Tumor Suppressor and Oncogenic Genes in Brazilian Malignant Pleural Mesotheliomas

Ligand-independent EGFR oligomers do not rely on the active state asymmetric kinase dimer

The Mutational Landscape of the SCAN-B Real-World Primary Breast Cancer Transcriptome

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