ERBB4 mutations in cancer and amyotrophic lateral sclerosis

ErbB receptor tyrosine kinases, epidermal growth factor receptor (EGFR, also known as ErbB1), ErbB2 (HER2 or NEU), ErbB3 (HER3), and ErbB4 (HER4), transduce signals borne by extracellular ligands into central cellular responses such as proliferation, survival, differentiation, and apoptosis. Mutations in ERBB genes are frequently detected in human malignant diseases of epithelial and neural origin, making ErbB receptors important drug targets. Targeting EGFR and ErbB2 has been successful in eg. lung and breast cancer, respectively, and mutations in these genes can be used to select patients that are responsive to the targeted treatment. Although somatic ERBB4 mutations have been found in many high-incidence cancers such as melanoma, lung cancer, and colorectal cancer and germ-line ERBB4 mutations have been linked to neuronal disorders and cancer, ErbB4 has generally been neglected as a potential drug target. Thus, the consequences of ERBB4 mutations on ErbB4 biology are largely unknown. This thesis aimed to elucidate the functional consequences and assess the clinical significance of somatic and germ-line ERBB4 mutations in the context of cancer and amyotrophic lateral sclerosis. The results of this study indicated that cancer-associated ERBB4 mutations can promote aberrant ErbB4 function by activating the receptor or inducing qualitative changes in ErbB4 signaling. ERBB4 mutations increased survival or decreased differentiation in vitro, suggesting that ERBB4 mutations can be oncogenic. Importantly, the potentially oncogenic mutations were located in various subdomains in ErbB4, possibly providing explanation for the characteristic scattered pattern of mutations in ERBB4. This study also demonstrated that hereditary variation in ERBB4 gene can have a significant effect on the prognosis of breast cancer. In addition, it was shown that hereditary or de novo germ-line ERBB4 mutations that predispose to amyotrophic lateral sclerosis inhibit ErbB4 activity. Together, these results suggest that ErbB4 should be considered as a novel drug target in cancer and amyotrophic lateral sclerosis.ERBB4-geenin mutaatiot syövässä ja amyotrofisessa lateraaliskleroosissa ErbB reseptorit, epidermaalisen kasvutekijän reseptori (EGFR tai ErbB1), ErbB2 (HER2 tai NEU), ErbB3 (HER3) ja ErbB4 (HER4), välittävät solun ulkopuolisten kasvutekijöiden tuomia signaaleja solun sisään, ja siten säätelevät keskeisiä solun toimintoja kuten kasvua, selviytymistä, erilaistumista ja kuolemaa. ERBB-geenien mutaatioita havaitaan toistuvasti eri syövissä. ErbB-reseptorit ovat merkittäviä lääkehoidon kohdemolekyylejä. Mutatoituneisiin EGFR- ja ErbB2-reseptoreihin kohdistettuja lääkehoitoja käytetään mm. keuhko- ja rintasyöpäpotilaiden hoidossa. Somaattisia ERBB4-geenin mutaatioita on havaittu useissa yleisissä syövissä kuten melanoomassa, keuhkosyövässä sekä paksu- ja peräsuolisyövässä. ERBB4-geenistä on tunnistettu myös monia ituradan mukana periytyviä mutaatioita keskushermoston sairauksissa ja syövissä. ErbB4-reseptorin merkitys lääkehoidon kohteena tunnetaan kuitenkin huonosti. Tässä tutkimuksessa pyrittiin selvittämään, miten ERBB4-geenin mutaatiot vaikuttavat reseptorin toimintaan, sekä arvioimaan ERBB4-geenin mutaatioiden kliinistä merkitystä syövässä ja amyotrofisessa lateraaliskleroosissa. Tutkimuksen tulokset osoittavat, että syövässä esiintyvät ERBB4 geenin mutaatiot voivat johtaa epänormaaliin reseptorin toimintaan joko aktivoimalla reseptorin, tai aiheuttamalla muutoksia reseptorin solunsisäisessä viestinvälityksessä. Nämä muutokset johtivat lisääntyneeseen syöpäsolujen selviytymiseen tai vähentyneeseen solujen erilaistumiseen in vitro. Tulosten perusteella ErbB4-reseptorin mutaatiot voivat olla onkogeenisiä. Huomionarvoista on, että nämä mahdollisesti onkogeeniset mutaatiot olivat jakaantuneet useaan ErbB4-reseptorin rakenteelliseen alayksiköön. Tutkimuksessa osoitetiin myös, että ERBB4-geenin perinnöllinen variaatio voi vaikuttaa rintasyöpäpotilaan taudin ennusteeseen. Lisäksi tutkimuksessa näytettiin, että ERBB4 geenin joko perinnölliset tai de novo ituradan mutaatiot, jotka altistavat amyotrofiselle lateraaliskleroosille, vähentävät ErbB4-reseptorin aktiivisuutta. Tulosten perusteella mutatoitunut ErbB4-reseptori voi olla potentiaalinen lääkehoidon kohde syövässä ja amyotrofisessaSiirretty Doriast

Good guy in bad company: How STRNs convert PP2A into an oncoprotein

Certain Protein Phosphatase 2A (PP2A) complexes are human tumor suppressors. In contrast, a paper in this issue of Cancer Cell and two other recent studies demonstrate that PP2A-STRN3/4 complexes inactivate Hippo tumor suppressor pathway, resulting in YAP activation and tumorigenesis. Furthermore, this new oncogenic phosphatase mechanism may be druggable</p

Työterveystoiminnan seurannan indikaattorit – työkyvyn hallinnan, seurannan ja varhaisen tuen prosessien indikaattorit

Väliraportissa käsitellään työterveyshuollon vaikuttavuutta sekä hankkeen tuloksia. Mukana ovat myös hankkeessa valmistuneet tarkistuslistat

Ecotoxicity impact assessment as a tool to study impacts of hazardous substances - a case study for ecotoxicity impacts of pesticide usage in Finland

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High frequency of BRAF V600E mutations in ameloblastoma

Peer reviewe

Deciphering the Structural Effects of Activating EGFR Somatic Mutations with Molecular Dynamics Simulation

Numerous somatic mutations occurring in the epidermal growth factor receptor (EGFR) family (ErbB) of receptor tyrosine kinases (RTK) have been reported from cancer patients, although relatively few have been tested and shown to cause functional changes in ErbBs. The ErbB receptors are dimerized and activated upon ligand binding, and dynamic conformational changes of the receptors are inherent for induction of downstream signaling. For two mutations shown experimentally to alter EGFR function, A702V and the Delta(746)ELREA(750) deletion mutation, we illustrate in the following protocol how molecular dynamics (MD) simulations can probe the (1) conformational stability of the mutant tyrosine kinase structure in comparison with wild-type EGFR; (2) structural consequences and conformational transitions and their relationship to observed functional changes; (3) effects of mutations on the strength of binding ATP as well as for binding between the kinase domains in the activated asymmetric dimer; and (4) effects of the mutations on key interactions within the EGFR binding site associated with the activated enzyme. The protocol provides a detailed step-by-step procedure as well as guidance that can be more generally useful for investigation of protein structures using MD simulations as a means to probe structural dynamics and the relationship to biological function

Structural Basis for the Functional Changes by EGFR Exon 20 Insertion Mutations

Simple SummaryNon-small cell lung cancer (NSCLC) is the most common type of lung cancer that claims the lives of many worldwide. Activating mutations occurring on the epidermal growth factor receptor (EGFR) protein have been associated with the pathogenesis of NSCLC, among which exon 20 insertion mutations play a significant role. The objective of this study is to examine the dynamic structural changes occurring on the EGFR protein as a result of two common EGFR exon 20 insertion mutations, V769insASV and D770insNPG. The study further aims to uncover the mechanisms by which the insertion mutations increase kinase activity. Our results suggest that the insertion mutations stabilize structural elements key to maintaining the active EGFR conformation. Furthermore, the insertions disrupt an interaction essential in stabilizing the inactive conformation, which could drive the kinase from an inactive to an active EGFR state. AbstractActivating somatic mutations of the epidermal growth factor receptor (EGFR) are frequently implicated in non-small cell lung cancer (NSCLC). While L858R and exon 19 deletion mutations are most prevalent, exon 20 insertions are often observed in NSCLC. Here, we investigated the structural implications of two common EGFR exon 20 insertions in NSCLC, V769insASV and D770insNPG. The active and inactive conformations of wild-type, D770insNPG and V769insASV EGFRs were probed with molecular dynamics simulations to identify local and global alterations that the mutations exert on the EGFR kinase domain, highlighting mechanisms for increased enzymatic activity. In the active conformation, the mutations increase interactions that stabilize the alpha C helix that is essential for EGFR activity. Moreover, the key Lys745-Glu762 salt bridge was more conserved in the insertion mutations. The mutants also preserved the state of the structurally critical aspartate-phenylalanine-glycine (DFG)-motif and regulatory spine (R-spine), which were altered in wild-type EGFR. The insertions altered the structure near the ATP-binding pocket, e.g., the P-loop, which may be a factor for the clinically observed tyrosine kinase inhibitor (TKI) insensitivity by the insertion mutants. The inactive state simulations also showed that the insertions disrupt the Ala767-Arg776 interaction that is key for maintaining the "alpha C-out" inactive conformation, which could consequently fuel the transition from the inactive towards the active EGFR state.</div

Identification of Predictive ERBB Mutations by Leveraging Publicly Available Cell Line Databases

While targeted therapies can be effective for a subgroup of patients, identification of individuals who benefit from the treatments is challenging. At the same time, the predictive significance of the vast majority of the thousands of mutations observed in the cancer tissues remains unknown. Here, we describe the identification of novel predictive biomarkers for ERBB-targeted tyrosine kinase inhibitors (TKI) by leveraging the genetic and drug screening data available in the public cell line databases: Cancer Cell Line Encyclopedia (CCLE), Genomics of Drug Sensitivity in Cancer (GDSC), and Cancer Therapeutics Response Portal (CTRP). We assessed the potential of 412 ERBB mutations in 296 cell lines to predict responses to 10 different ERBB-targeted TKIs. Seventy-six ERBB mutations were identified that were associated with ERBB TKI sensitivity comparable to non-small cell lung cancer cell lines harboring the well-established predictive EGFR L858R mutation or exon 19 deletions. Fourteen (18.4 %) of these mutations were classified as oncogenic by the cBioPortal database, whereas 62 (81.6 %) were regarded as novel potentially predictive mutations. Out of nine functionally validated novel mutations, EGFR Y1069C and ERBB2 E936K were transforming in Ba/F3 cells and demonstrated enhanced signaling activity. Mechanistically, the EGFR Y1069C mutation disrupted the binding of the ubiquitin ligase c-CBL to EGFR, whereas the ERBB2 E936K mutation selectively enhanced the activity of ERBB heterodimers. These findings indicate that integrating data from publicly available cell line databases can be used to identify novel, predictive non-hotspot mutations, potentially expanding the patient population benefiting from existing cancer therapies

ERBB4 Promoter Polymorphism Is Associated with Poor Distant Disease-Free Survival in High-Risk Early Breast Cancer

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