Efficacy of osimertinib against EGFRvIII+ glioblastoma

Chagoya, Gustavo; Kwatra, Shawn G.; Nanni, Cory; Roberts, Callie; Phillips, S.; Nullmeyergh, Sarah; Gilmore, Samuel P.; Spasojević, Ivan; Corcoran, David L.; Young, Christopher C.; Ballman, Karla V.; Ramakrishna, Rohan; Cross, Darren A.E.; Markert, James M.; Lim, Michael; Gilbert, Mark R.; Lesser, Glenn J.; Kwatra, Madan M.

doi:10.18632/oncotarget.27599

Cited by 45 publications

(34 citation statements)

References 31 publications

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“…Systemic OS treatment effectively inhibited the EGFR-TAZ signal and xenograft growth in two orthotopic GBM xenograft models, including an aggressive EGFRvIII + model, justifying the clinical evaluation of OS in GBM. This result is also consistent with a recent publication supporting the pre-clinical efficacy of this drug on EGFRvIII + GBM models (49). It is noteworthy to mention that OS downregulates validated TAZ-Up genes (e.g.…”

Section: Discussionsupporting

confidence: 92%

EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma

Gao

Zhou

et al. 2021

Cancer Research

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Hyperactivated EGFR signaling is a driver of various human cancers, including glioblastoma (GBM). Effective EGFR-targeted therapies rely on knowledge of key signaling hubs that transfer and amplify EGFR signaling. Here we focus on the transcription factor TAZ, a potential signaling hub in the EGFR signaling network. TAZ expression was positively associated with EGFR expression in clinical GBM specimens.In patient-derived GBM neurospheres, EGF induced TAZ through EGFR-ERK and EGFR-STAT3 signaling, and the constitutively active EGFRvIII mutation caused EGFindependent hyperactivation of TAZ. Genome-wide analysis showed that the EGFR-TAZ axis activates multiple oncogenic signaling mechanisms, including an EGFR-TAZ-RTK positive feedback loop, as well as upregulating HIF1α and other oncogenic genes.TAZ hyperactivation in GBM stem-like cells induced exogenous mitogen-independent growth and promoted GBM invasion, radioresistance, and tumorigenicity. Screening a panel of brain-penetrating EGFR inhibitors identified osimertinib as the most potent inhibitor of the EGFR-TAZ signaling axis. Systemic osimertinib treatment inhibited the EGFR-TAZ axis and in vivo growth of GBM stem-like cell xenografts. Overall these results show that the therapeutic efficacy of osimertinib relies on effective TAZ inhibition, thus identifying TAZ as a potential biomarker of osimertinib sensitivity.

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Section: Discussionsupporting

confidence: 92%

EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma

Gao

Zhou

et al. 2021

Cancer Research

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“…The third-generation EGFR inhibitors include AZD9291 (osimertinib) and AEE788 (everolimus). Preclinically, AZD9291 proved to have better activity and selectivity for GB than the previous inhibitors, thereby overcoming primary resistance by continuously blocking ERK signaling [ 82 , 83 ]. In a case report, AZD9291 demonstrated clinical activity and a phase II study in recurrent GB patients is currently in the recruitment phase (NCT03732352) [ 67 , 84 ].…”

Section: Receptor Tyrosine Kinase Inhibitors (Rtkis) For Gb Therapymentioning

confidence: 99%

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

et al. 2021

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Glioblastoma (GB) remains the most fatal brain tumor characterized by a high infiltration rate and treatment resistance. Overexpression and/or mutation of receptor tyrosine kinases is common in GB, which subsequently leads to the activation of many downstream pathways that have a critical impact on tumor progression and therapy resistance. Therefore, receptor tyrosine kinase inhibitors (RTKIs) have been investigated to improve the dismal prognosis of GB in an effort to evolve into a personalized targeted therapy strategy with a better treatment outcome. Numerous RTKIs have been approved in the clinic and several radiopharmaceuticals are part of (pre)clinical trials as a non-invasive method to identify patients who could benefit from RTKI. The latter opens up the scope for theranostic applications. In this review, the present status of RTKIs for the treatment, nuclear imaging and targeted radionuclide therapy of GB is presented. The focus will be on seven tyrosine kinase receptors, based on their central role in GB: EGFR, VEGFR, MET, PDGFR, FGFR, Eph receptor and IGF1R. Finally, by way of analyzing structural and physiological characteristics of the TKIs with promising clinical trial results, four small molecule RTKIs were selected based on their potential to become new therapeutic GB radiopharmaceuticals.

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“…An enduring puzzle in clinical GB research has been the robust data showing that EGFR, mutated or just EGFR overexpressed, commonly drives growth in both NSCLC and GB, yet older, non-osimertinib EGFR inhibitors such as erlotinib and gefitinib anti-EGFR treatments commonly benefit in NSCLC, but have utterly failed to benefit in GB [ 13 ]. An EGFR mutation, EGFRvIII is commonly found in GB and osimertinib inhibits this with an IC50 <100 nM, and in a preclinical study, osimertinib inhibited EGFRvIII-positive GB growth In Vitro and in an orthotopic xenograft model [ 14 ]. Thus, an osimertinib clinical trial in GB—with or without OPALS adjuvant—would be eminently worthwhile.…”

Section: Osimertinibmentioning

confidence: 99%

OPALS: A New Osimertinib Adjunctive Treatment of Lung Adenocarcinoma or Glioblastoma Using Five Repurposed Drugs

Kast¹,

Halatsch

Rosell

2021

Cells

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Background: Pharmacological targeting aberrant activation of epidermal growth factor receptor tyrosine kinase signaling is an established approach to treating lung adenocarcinoma. Osimertinib is a tyrosine kinase approved and effective in treating lung adenocarcinomas that have one of several common activating mutations in epidermal growth factor receptor. The emergence of resistance to osimertinib after a year or two is the rule. We developed a five-drug adjuvant regimen designed to increase osimertinib’s growth inhibition and thereby delay the development of resistance. Areas of Uncertainty: Although the assembled preclinical data is strong, preclinical data and the following clinical trial results can be discrepant. The safety of OPALS drugs when used individually is excellent. We have no data from humans on their tolerability when used as an ensemble. That there is no data from the individual drugs to suspect problematic interaction does not exclude the possibility. Data Sources: All relevant PubMed.org articles on the OPALS drugs and corresponding pathophysiology of lung adenocarcinoma and glioblastoma were reviewed. Therapeutic Opinion: The five drugs of OPALS are in wide use in general medicine for non-oncology indications. OPALS uses the anti-protozoal drug pyrimethamine, the antihistamine cyproheptadine, the antibiotic azithromycin, the antihistamine loratadine, and the potassium sparing diuretic spironolactone. We show how these inexpensive and generically available drugs intersect with and inhibit lung adenocarcinoma growth drive. We also review data showing that both OPALS adjuvant drugs and osimertinib have data showing they may be active in suppressing glioblastoma growth.

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Efficacy of osimertinib against EGFRvIII+ glioblastoma

Cited by 45 publications

References 31 publications

EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma

EGFR Activates a TAZ-Driven Oncogenic Program in Glioblastoma

Novel Receptor Tyrosine Kinase Pathway Inhibitors for Targeted Radionuclide Therapy of Glioblastoma

OPALS: A New Osimertinib Adjunctive Treatment of Lung Adenocarcinoma or Glioblastoma Using Five Repurposed Drugs

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