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EGFRvIII tumorigenicity requires PDGFRA co-signaling and reveals therapeutic vulnerabilities in glioblastoma

Oncogene volume 40, pages 2682–2696 (2021)Cite this article

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Abstract

Focal amplification of epidermal growth factor receptor (EGFR) and its ligand-independent, constitutively active EGFRvIII mutant form are prominent oncogenic drivers in glioblastoma (GBM). The EGFRvIII gene rearrangement is considered to be an initiating event in the etiology of GBM, however, the mechanistic details of how EGFRvIII drives cellular transformation and tumor maintenance remain unclear. Here, we report that EGFRvIII demonstrates a reliance on PDGFRA co-stimulatory signaling during the tumorigenic process in a genetically engineered autochthonous GBM model. This dependency exposes liabilities that were leveraged using kinase inhibitors treatments in EGFRvIII-expressing GBM patient-derived xenografts (PDXs), where simultaneous pharmacological inhibition of EGFRvIII and PDGFRA kinase activities is necessary for anti-tumor efficacy. Our work establishes that EGFRvIII-positive tumors have unexplored vulnerabilities to targeted agents concomitant to the EGFR kinase inhibitor repertoire.

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Fig. 1: Canertinib treatments induce apoptosis in EGFRvIII GBM PDXs.
Fig. 2: Antigrowth efficacy of Canertinib in vivo.
Fig. 3: Canertinib treatment decreases the activity of PDGFRA and demonstrates dose-dependent antitumor activity.
Fig. 4: Simultaneous inhibition of MEK1/2 and PI3K signaling is necessary to trigger apoptosis in GBM6 PDX cells.
Fig. 5: Inhibition of PDGFRA sensitizes GBM PDX cells to EGFR inhibition.
Fig. 6: EGFRvIII expression requires co-signaling for cellular transformation in vitro and GBM tumor formation in vivo.
Fig. 7: PDGFRA activation cooperates with EGFRvIII to initiate GBM tumorigenesis in vivo.

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References

  1. Brennan CW, Verhaak RG, McKenna A, Campos B, Noushmehr H, Salama SR, et al. The somatic genomic landscape of glioblastoma. Cell. 2013;155:462–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. McLendon R, Friedman A, Bigner D, Van Meir EG, Brat DJ, Mastrogianakis M, et al. Comprehensive genomic characterization defines human glioblastoma genes and core pathways. Nature. 2008;455:1061–8.

    Article  CAS  Google Scholar 

  3. Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, et al. Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell. 2010;17:98–110.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Verhaak RGW, Bafna V, Mischel PS. Extrachromosomal oncogene amplification in tumour pathogenesis and evolution. Nat Rev Cancer. 2019;19:283–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. deCarvalho AC, Kim H, Poisson LM, Winn ME, Mueller C, Cherba D, et al. Discordant inheritance of chromosomal and extrachromosomal DNA elements contributes to dynamic disease evolution in glioblastoma. Nat Genet. 2018;50:708–17.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Turner KM, Deshpande V, Beyter D, Koga T, Rusert J, Lee C, et al. Extrachromosomal oncogene amplification drives tumour evolution and genetic heterogeneity. Nature. 2017;543:122–5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Nathanson DA, Gini B, Mottahedeh J, Visnyei K, Koga T, Gomez G, et al. Targeted therapy resistance mediated by dynamic regulation of extrachromosomal mutant EGFR DNA. Science. 2014;343:72–76.

    Article  CAS  PubMed  Google Scholar 

  8. Shinojima N, Tada K, Shiraishi S, Kamiryo T, Kochi M, Nakamura H, et al. Prognostic value of epidermal growth factor receptor in patients with glioblastoma multiforme. Cancer Res. 2003;63:6962–70.

    CAS  PubMed  Google Scholar 

  9. Heimberger AB, Hlatky R, Suki D, Yang D, Weinberg J, Gilbert M, et al. Prognostic effect of epidermal growth factor receptor and EGFRvIII in glioblastoma multiforme patients. Clin Cancer Res. 2005;11:1462–6.

    Article  CAS  PubMed  Google Scholar 

  10. Kastenhuber ER, Huse JT, Berman SH, Pedraza A, Zhang J, Suehara Y, et al. Quantitative assessment of intragenic receptor tyrosine kinase deletions in primary glioblastomas: their prevalence and molecular correlates. Acta Neuropathol. 2014;127:747–59.

    Article  CAS  PubMed  Google Scholar 

  11. Weller M, Felsberg J, Hartmann C, Berger H, Steinbach JP, Schramm J, et al. Molecular predictors of progression-free and overall survival in patients with newly diagnosed glioblastoma: a prospective translational study of the German Glioma Network. J Clin Oncol. 2009;27:5743–50.

    Article  CAS  PubMed  Google Scholar 

  12. Felsberg J, Hentschel B, Kaulich K, Gramatzki D, Zacher A, Malzkorn B, et al. Epidermal growth factor receptor variant III (EGFRvIII) positivity in EGFR-amplified glioblastomas: prognostic role and comparison between primary and recurrent tumors. Clin Cancer Res. 2017;23:6846–55.

    Article  CAS  PubMed  Google Scholar 

  13. van den Bent MJ, Gao Y, Kerkhof M, Kros JM, Gorlia T, van Zwieten K, et al. Changes in the EGFR amplification and EGFRvIII expression between paired primary and recurrent glioblastomas. Neurooncology. 2015;17:935–41.

    Google Scholar 

  14. Montano N, Cenci T, Martini M, D’Alessandris QG, Pelacchi F, Ricci-Vitiani L, et al. Expression of EGFRvIII in glioblastoma: prognostic significance revisited. Neoplasia. 2011;13:1113–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Patel AP, Tirosh I, Trombetta JJ, Shalek AK, Gillespie SM, Wakimoto H, et al. Single-cell RNA-seq highlights intratumoral heterogeneity in primary glioblastoma. Science. 2014;344:1396–401.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Meyer M, Reimand J, Lan X, Head R, Zhu X, Kushida M, et al. Single cell-derived clonal analysis of human glioblastoma links functional and genomic heterogeneity. Proc Natl Acad Sci USA. 2015;112:851–6.

    Article  CAS  PubMed  Google Scholar 

  17. Darmanis S, Sloan SA, Croote D, Mignardi M, Chernikova S, Samghababi P, et al. Single-cell RNA-seq analysis of infiltrating neoplastic cells at the migrating front of human glioblastoma. Cell Rep. 2017;21:1399–410.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Francis JM, Zhang CZ, Maire CL, Jung J, Manzo VE, Adalsteinsson VA, et al. EGFR variant heterogeneity in glioblastoma resolved through single-nucleus sequencing. Cancer Discov. 2014;4:956–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Nishikawa R, Sugiyama T, Narita Y, Furnari F, Cavenee WK, Matsutani M. Immunohistochemical analysis of the mutant epidermal growth factor, δEGFR, in glioblastoma. Brain Tumor Pathol. 2004;21:53–56.

    Article  CAS  PubMed  Google Scholar 

  20. Fan QW, Cheng CK, Gustafson WC, Charron E, Zipper P, Wong RA, et al. EGFR phosphorylates tumor-derived EGFRvIII driving STAT3/5 and progression in glioblastoma. Cancer Cell. 2013;24:438–49.

    Article  CAS  PubMed  Google Scholar 

  21. Rutkowska A, Stoczynska-Fidelus E, Janik K, Wlodarczyk A, Rieske P. EGFR(vIII): an oncogene with ambiguous role. J Oncol. 2019;2019:1092587.

    Article  PubMed  PubMed Central  Google Scholar 

  22. Gan HK, Cvrljevic AN, Johns TG. The epidermal growth factor receptor variant III (EGFRvIII): where wild things are altered. FEBS J. 2013;280:5350–70.

    Article  CAS  PubMed  Google Scholar 

  23. Lemmon MA, Schlessinger J, Ferguson KM. The EGFR family: not so prototypical receptor tyrosine kinases. Cold Spring Harb Perspect Biol. 2014;6:a020768.

    Article  PubMed  PubMed Central  Google Scholar 

  24. Stec W, Rosiak K, Treda C, Smolarz M, Peciak J, Pacholczyk M, et al. Cyclic trans-phosphorylation in a homodimer as the predominant mechanism of EGFRvIII action and regulation. Oncotarget. 2018;9:8560–72.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Gajadhar AS, Bogdanovic E, Munoz DM, Guha A. In situ analysis of mutant EGFRs prevalent in glioblastoma multiforme reveals aberrant dimerization, activation, and differential response to anti-EGFR targeted therapy. Mol Cancer Res. 2012;10:428–40.

    Article  CAS  PubMed  Google Scholar 

  26. Hwang Y, Chumbalkar V, Latha K, Bogler O. Forced dimerization increases the activity of DeltaEGFR/EGFRvIII and enhances its oncogenicity. Mol Cancer Res. 2011;9:1199–208.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kancha RK, von Bubnoff N, Duyster J. Asymmetric kinase dimer formation is crucial for the activation of oncogenic EGFRvIII but not for ERBB3 phosphorylation. Cell Commun Signal. 2013;11:39.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Fernandes H, Cohen S, Bishayee S. Glycosylation-induced conformational modification positively regulates receptor-receptor association: a study with an aberrant epidermal growth factor receptor (EGFRvIII/DeltaEGFR) expressed in cancer cells. J Biol Chem. 2001;276:5375–83.

    Article  CAS  PubMed  Google Scholar 

  29. Luwor RB, Zhu HJ, Walker F, Vitali AA, Perera RM, Burgess AW, et al. The tumor-specific de2-7 epidermal growth factor receptor (EGFR) promotes cells survival and heterodimerizes with the wild-type EGFR. Oncogene. 2004;23:6095–104.

    Article  CAS  PubMed  Google Scholar 

  30. Greenall SA, Donoghue JF, Van Sinderen M, Dubljevic V, Budiman S, Devlin M, et al. EGFRvIII-mediated transactivation of receptor tyrosine kinases in glioma: mechanism and therapeutic implications. Oncogene. 2015;34:5277–87.

    Article  CAS  PubMed  Google Scholar 

  31. Ymer SI, Greenall SA, Cvrljevic A, Cao DX, Donoghue JF, Epa VC, et al. Glioma specific extracellular missense mutations in the first cysteine rich region of epidermal growth factor receptor (EGFR) initiate ligand independent activation. Cancers. 2011;3:2032–49.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Paul MD, Hristova K. The RTK interactome: overview and perspective on RTK heterointeractions. Chem Rev. 2019;119:5881–921.

    Article  CAS  PubMed  Google Scholar 

  33. Chakravarty D, Pedraza AM, Cotari J, Liu AH, Punko D, Kokroo A, et al. EGFR and PDGFRA co-expression and heterodimerization in glioblastoma tumor sphere lines. Sci Rep. 2017;7:9043.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Garnett J, Chumbalkar V, Vaillant B, Gururaj AE, Hill KS, Latha K, et al. Regulation of HGF expression by DeltaEGFR-mediated c-Met activation in glioblastoma cells. Neoplasia. 2013;15:73–84.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Szerlip NJ, Pedraza A, Chakravarty D, Azim M, McGuire J, Fang Y, et al. Intratumoral heterogeneity of receptor tyrosine kinases EGFR and PDGFRA amplification in glioblastoma defines subpopulations with distinct growth factor response. Proc Natl Acad Sci USA. 2012;109:3041–6.

    Article  CAS  PubMed  Google Scholar 

  36. Chen PH, Chen X, He X. Platelet-derived growth factors and their receptors: structural and functional perspectives. Biochim Biophys Acta. 2013;1834:2176–86.

    Article  CAS  PubMed  Google Scholar 

  37. Jun HJ, Appleman VA, Wu HJ, Rose CM, Pineda JJ, Yeo AT, et al. A PDGFRalpha-driven mouse model of glioblastoma reveals a stathmin1-mediated mechanism of sensitivity to vinblastine. Nat Commun. 2018;9:3116.

    Article  PubMed  PubMed Central  Google Scholar 

  38. Zhou S, Appleman VA, Rose CM, Jun HJ, Yang J, Zhou Y, et al. Chronic platelet-derived growth factor receptor signaling exerts control over initiation of protein translation in glioma. Life Sci Alliance. 2018;1:e201800029.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Roskoski R Jr. Small molecule inhibitors targeting the EGFR/ErbB family of protein-tyrosine kinases in human cancers. Pharm Res. 2019;139:395–411.

    Article  CAS  Google Scholar 

  40. Reardon DA, Wen PY, Mellinghoff IK. Targeted molecular therapies against epidermal growth factor receptor: past experiences and challenges. Neurooncology. 2014;16:viii7–13.

    CAS  Google Scholar 

  41. Sarkaria JN, Yang L, Grogan PT, Kitange GJ, Carlson BL, Schroeder MA, et al. Identification of molecular characteristics correlated with glioblastoma sensitivity to EGFR kinase inhibition through use of an intracranial xenograft test panel. Mol Cancer Ther. 2007;6:1167–74.

    Article  CAS  PubMed  Google Scholar 

  42. Sarkaria JN, Carlson BL, Schroeder MA, Grogan P, Brown PD, Giannini C, et al. Use of an orthotopic xenograft model for assessing the effect of epidermal growth factor receptor amplification on glioblastoma radiation response. Clin Cancer Res. 2006;12:2264–71.

    Article  CAS  PubMed  Google Scholar 

  43. Vaubel RA, Tian S, Remonde D, Schroeder MA, Mladek AC, Kitange GJ, et al. Genomic and phenotypic characterization of a broad panel of patient-derived xenografts reflects the diversity of glioblastoma. Clin Cancer Res. 2020;26:1094–104.

    Article  CAS  PubMed  Google Scholar 

  44. Davis MI, Hunt JP, Herrgard S, Ciceri P, Wodicka LM, Pallares G, et al. Comprehensive analysis of kinase inhibitor selectivity. Nat Biotechnol. 2011;29:1046–51.

    Article  CAS  PubMed  Google Scholar 

  45. Folkes AJ, Ahmadi K, Alderton WK, Alix S, Baker SJ, Box G, et al. The identification of 2-(1H-indazol-4-yl)-6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-t hieno[3,2-d]pyrimidine (GDC-0941) as a potent, selective, orally bioavailable inhibitor of class I PI3 kinase for the treatment of cancer. J Med Chem. 2008;51:5522–32.

    Article  CAS  PubMed  Google Scholar 

  46. Brown AP, Carlson TC, Loi CM, Graziano MJ. Pharmacodynamic and toxicokinetic evaluation of the novel MEK inhibitor, PD0325901, in the rat following oral and intravenous administration. Cancer Chemother Pharm. 2007;59:671–9.

    Article  CAS  Google Scholar 

  47. Roskoski R Jr. The role of small molecule platelet-derived growth factor receptor (PDGFR) inhibitors in the treatment of neoplastic disorders. Pharmacol Res. 2018;129:65–83.

    Article  CAS  PubMed  Google Scholar 

  48. Zhu H, Acquaviva J, Ramachandran P, Boskovitz A, Woolfenden S, Pfannl R, et al. Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis. Proc Natl Acad Sci USA. 2009;106:2712–6.

    Article  CAS  PubMed  Google Scholar 

  49. Stommel JM, Kimmelman AC, Ying H, Nabioullin R, Ponugoti AH, Wiedemeyer R, et al. Coactivation of receptor tyrosine kinases affects the response of tumor cells to targeted therapies. Science. 2007;318:287–90.

    Article  CAS  PubMed  Google Scholar 

  50. McNeill RS, Canoutas DA, Stuhlmiller TJ, Dhruv HD, Irvin DM, Bash RE, et al. Combination therapy with potent PI3K and MAPK inhibitors overcomes adaptive kinome resistance to single agents in preclinical models of glioblastoma. Neuro-oncology. 2017;19:1469–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Schram AM, Gandhi L, Mita MM, Damstrup L, Campana F, Hidalgo M, et al. A phase Ib dose-escalation and expansion study of the oral MEK inhibitor pimasertib and PI3K/MTOR inhibitor voxtalisib in patients with advanced solid tumours. Br J Cancer. 2018;119:1471–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Wainberg ZA, Alsina M, Soares HP, Brana I, Britten CD, Del Conte G, et al. A multi-arm phase I study of the PI3K/mTOR inhibitors PF-04691502 and gedatolisib (PF-05212384) plus irinotecan or the MEK inhibitor PD-0325901 in advanced cancer. Target Oncol. 2017;12:775–85.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Grilley-Olson JE, Bedard PL, Fasolo A, Cornfeld M, Cartee L, Razak AR, et al. A phase Ib dose-escalation study of the MEK inhibitor trametinib in combination with the PI3K/mTOR inhibitor GSK2126458 in patients with advanced solid tumors. Investig New Drugs. 2016;34:740–9.

    Article  CAS  Google Scholar 

  54. Bedard PL, Tabernero J, Janku F, Wainberg ZA, Paz-Ares L, Vansteenkiste J, et al. A phase Ib dose-escalation study of the oral pan-PI3K inhibitor buparlisib (BKM120) in combination with the oral MEK1/2 inhibitor trametinib (GSK1120212) in patients with selected advanced solid tumors. Clin Cancer Res. 2015;21:730–8.

    Article  CAS  PubMed  Google Scholar 

  55. Tolcher AW, Patnaik A, Papadopoulos KP, Rasco DW, Becerra CR, Allred AJ, et al. Phase I study of the MEK inhibitor trametinib in combination with the AKT inhibitor afuresertib in patients with solid tumors and multiple myeloma. Cancer Chemother Pharm. 2015;75:183–9.

    Article  CAS  Google Scholar 

  56. Bachoo RM, Maher EA, Ligon KL, Sharpless NE, Chan SS, You MJ, et al. Epidermal growth factor receptor and Ink4a/Arf: convergent mechanisms governing terminal differentiation and transformation along the neural stem cell to astrocyte axis. Cancer Cell. 2002;1:269–77.

    Article  CAS  PubMed  Google Scholar 

  57. Xing Y, Wang R, Li C, Minoo P. PTEN regulates lung endodermal morphogenesis through MEK/ERK pathway. Dev Biol. 2015;408:56–65.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Gu J, Tamura M, Yamada KM. Tumor suppressor PTEN inhibits integrin- and growth factor-mediated mitogen-activated protein (MAP) kinase signaling pathways. J Cell Biol. 1998;143:1375–83.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Ebbesen SH, Scaltriti M, Bialucha CU, Morse N, Kastenhuber ER, Wen HY, et al. Pten loss promotes MAPK pathway dependency in HER2/neu breast carcinomas. Proc Natl Acad Sci USA. 2016;113:3030–5.

    Article  CAS  PubMed  Google Scholar 

  60. Weng LP, Smith WM, Brown JL, Eng C. PTEN inhibits insulin-stimulated MEK/MAPK activation and cell growth by blocking IRS-1 phosphorylation and IRS-1/Grb-2/Sos complex formation in a breast cancer model. Hum Mol Genet. 2001;10:605–16.

    Article  CAS  PubMed  Google Scholar 

  61. Wee S, Jagani Z, Xiang KX, Loo A, Dorsch M, Yao YM, et al. PI3K pathway activation mediates resistance to MEK inhibitors in KRAS mutant cancers. Cancer Res. 2009;69:4286–93.

    Article  CAS  PubMed  Google Scholar 

  62. Weng LP, Brown JL, Baker KM, Ostrowski MC, Eng C. PTEN blocks insulin-mediated ETS-2 phosphorylation through MAP kinase, independently of the phosphoinositide 3-kinase pathway. Hum Mol Genet. 2002;11:1687–96.

    Article  CAS  PubMed  Google Scholar 

  63. Snuderl M, Fazlollahi L, Le LP, Nitta M, Zhelyazkova BH, Davidson CJ, et al. Mosaic amplification of multiple receptor tyrosine kinase genes in glioblastoma. Cancer Cell. 2011;20:810–7.

    Article  CAS  PubMed  Google Scholar 

  64. Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA. Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996;85:27–37.

    Article  CAS  PubMed  Google Scholar 

  65. Lesche R, Groszer M, Gao J, Wang Y, Messing A, Sun H, et al. Cre/loxP-mediated inactivation of the murine Pten tumor suppressor gene. Genesis. 2002;32:148–9.

    Article  CAS  PubMed  Google Scholar 

  66. Shin KJ, Wall EA, Zavzavadjian JR, Santat LA, Liu J, Hwang JI, et al. A single lentiviral vector platform for microRNA-based conditional RNA interference and coordinated transgene expression. Proc Natl Acad Sci USA. 2006;103:13759–64.

    Article  CAS  PubMed  Google Scholar 

  67. Madisen L, Zwingman TA, Sunkin SM, Oh SW, Zariwala HA, Gu H, et al. A robust and high-throughput Cre reporting and characterization system for the whole mouse brain. Nat Neurosci. 2010;13:133–40.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

The authors thank Drs. Shruti Rawal and Shibani Mukherjee for critical review of the manuscript. The authors also thank Patrick Hyland (Tufts University), Ilyse Blazar (Boston University), Derrek Schartz (Tufts University) for their technical assistance. This work was supported by NIH grants R01 CA229784 and R21 CA245337 to AC and by internal funding to the Mayo Clinic GBM PDX National Resource to JNS.

Funding

This work was supported by NIH grants R01 CA229784 and R21 CA245337 to AC and by internal funding to the Mayo Clinic GBM PDX National Resource to JNS.

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Authors and Affiliations

  1. Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Alan T. Yeo, Hyun Jung Jun, Vicky A. Appleman, Piyan Zhang & Al Charest

  2. Sackler School of Graduate Studies, Tufts University School of Medicine, Boston, MA, USA

    Alan T. Yeo

  3. Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA

    Hemant Varma

  4. Department of Radiation Oncology, Mayo Clinic, Rochester, MN, USA

    Jann N. Sarkaria

  5. Cancer Research Institute, Beth Israel Deaconess Medical Center, Boston, MA, USA

    Al Charest

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Yeo, A.T., Jun, H.J., Appleman, V.A. et al. EGFRvIII tumorigenicity requires PDGFRA co-signaling and reveals therapeutic vulnerabilities in glioblastoma. Oncogene 40, 2682–2696 (2021). https://doi.org/10.1038/s41388-021-01721-9

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