Abstract 5739
Background
Mutation of either the intracellular catalytic domain or the extracellular domain of the receptor for epidermal growth factor (EGFR) drives oncogenicity. Extracellular domain EGFR mutations are highly expressed in patients with glioblastoma. Despite clinical success with targeting EGFR catalytic site mutants, no drugs have proven effective in glioblastoma patients expressing extracellular EGFR mutations.
Methods
Herein, we define the molecular mechanism for oncogenic activation of families of extracellular EGFR mutations and reveal how this mechanism renders current generation small molecule ATP-site inhibitors ineffective. We define these types of lesions as allosteric oncogenic mutations.
Results
We demonstrate that a group of the most commonly expressed extracellular domain EGFR mutants expressed in glioblastomas is activated by disulfide-bond mediated covalent homodimerization, collectively referred to as locked dimerization (LoDi-EGFR oncogenes). Strikingly, current generation small molecules binding to the active kinase conformation potently inhibit catalytic site mutants, but induce covalent dimerization and activate LoDi-EGFR receptors, manifesting in paradoxical acceleration of proliferation. Herein we describe the discovery of novel ATP competitive small molecules that potently (<50nM) inhibit the family of LoDi-EGFR oncogenes expressed in GBM, and importantly, achieve selectivity versus WT-EGFR of greater than 10-fold.
Conclusions
These data demonstrate how the locked-dimer mechanism of EGFR oncogenesis has profound impact on the activity of small molecules acting at the distal catalytic site, providing further evidence for “inside-out” allosteric signaling in EGFR. This provides a mechanistic understanding for the failure of current generation EGFR inhibitors to effectively treat LoDi-EGFR mutants in GBM and sets guidelines for the discovery and development of novel selective LoDi-EGFR inhibitors.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Black Diamond Therapeutics.
Funding
Black Diamond Therapeutics.
Disclosure
E. Buck: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Black Diamond Therapeutics. M. O’Connor: Leadership role, Shareholder / Stockholder / Stock options, Full / Part-time employment: Black Diamond Therapeutics. A. Flohr: Leadership role, Shareholder / Stockholder / Stock options: Black Diamond Therapeutics. R. Iacone: Leadership role, Shareholder / Stockholder / Stock options: Black Diamond Therapeutics. A.V. Mayweg: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Black Diamond Therapeutics. D.M. Epstein: Leadership role, Shareholder / Stockholder / Stock options, Officer / Board of Directors: Black Diamond Therapeutics. All other authors have declared no conflicts of interest.
Resources from the same session
4526 - Long-term outcome of neoadjuvant tyrosine kinase inhibitors (TKI) in locally advanced dermatofibrosarcoma protuberans (DFSP)
Presenter: Jessica Beaziz
Session: Poster Display session 1
Resources:
Abstract
1214 - Neo-adjuvant (NA) Imatinib for gastrointestinal stromal tumours (GISTs): What is the optimal length of treatment?
Presenter: Tom Wilson
Session: Poster Display session 1
Resources:
Abstract
2690 - Gastrointestinal Stromal Tumours (GIST) in adolescents and young adults (AYA)
Presenter: Nikki Ijzerman
Session: Poster Display session 1
Resources:
Abstract
4558 - Radiomics improves response evaluation for desmoid tumors treated with chemotherapy
Presenter: Amandine Crombe
Session: Poster Display session 1
Resources:
Abstract
2751 - Radiomics of gastrointestinal stromal tumors; risk classification based on computed tomography images – a pilot study
Presenter: Milea Timbergen
Session: Poster Display session 1
Resources:
Abstract
2737 - Differentiating well-differentiated liposarcomas from lipomas using a radiomics approach
Presenter: Melissa Vos
Session: Poster Display session 1
Resources:
Abstract
1282 - The immune landscape of chondrosarcoma reveals an anti inflammatory environment
Presenter: Iseulys Richert
Session: Poster Display session 1
Resources:
Abstract
1572 - Impact of Immunotherapy and Targeted Therapy on Tumor Growth Rate in Sarcoma
Presenter: Esmail Al-ezzi
Session: Poster Display session 1
Resources:
Abstract
3414 - DNA methylation profiles of angiosarcoma subtypes.
Presenter: Marije Weidema
Session: Poster Display session 1
Resources:
Abstract
3411 - Prognostic significance of circulating PD-1, PD-L1, pan-BTN3As and BTN3A1 in patients with metastatic gastrointestinal stromal tumors (mGISTs)
Presenter: Daniele Fanale
Session: Poster Display session 1
Resources:
Abstract