Skip to main content
OSTI.GOVU.S. Department of Energy Office of Scientific and Technical Information
U.S. Department of Energy
Office of Scientific and Technical Information
 

Single and Dual Targeting of Mutant EGFR with an Allosteric Inhibitor

Journal Article · · Cancer Discovery
 [1];  [1];  [2];  [1];  [2];  [1];  [3];  [3];  [4];  [1];  [1];  [1];  [2];  [2];  [5];  [1];  [1];  [5]
  1. Dana-Farber Cancer Inst., Boston, MA (United States); Harvard Medical School, Boston, MA (United States)
  2. Dana-Farber Cancer Inst., Boston, MA (United States)
  3. Belfer Center for Applied Cancer Science, Boston, MA (United States)
  4. Scripps Research Inst., Jupiter, FL (United States)
  5. Dana-Farber Cancer Inst., Boston, MA (United States); Harvard Medical School, Boston, MA (United States); Belfer Center for Applied Cancer Science, Boston, MA (United States)
+ Show Author Affiliations

Allosteric kinase inhibitors offer a potentially complementary therapeutic strategy to ATP-competitive kinase inhibitors due to their distinct sites of target binding. Here, we identify and study a mutant-selective EGFR allosteric inhibitor, JBJ-04-125-02, which as a single agent can inhibit cell proliferation and EGFRL858R/T790M/C797S signaling in vitro and in vivo. However, increased EGFR dimer formation limits treatment efficacy and leads to drug resistance. Remarkably, osimertinib, an ATP-competitive covalent EGFR inhibitor, uniquely and significantly enhances the binding of JBJ-04-125-02 for mutant EGFR. The combination of osimertinib and JBJ-04-125-02 results in an increase in apoptosis, a more effective inhibition of cellular growth, and an increased efficacy in vitro and in vivo compared with either single agent alone. Collectively, our findings suggest that the combination of a covalent mutant–selective ATP-competitive inhibitor and an allosteric EGFR inhibitor may be an effective therapeutic approach for patients with EGFR-mutant lung cancer. Significance: The clinical efficacy of EGFR tyrosine kinase inhibitors (TKI) in EGFR-mutant lung cancer is limited by acquired drug resistance, thus highlighting the need for alternative strategies to inhibit EGFR. Here, we identify a mutant EGFR allosteric inhibitor that is effective as a single agent and in combination with the EGFR TKI osimertinib.

Research Organization:
Argonne National Laboratory (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Organization:
USDOE Office of Science (SC); National Cancer Institute (NCI); American Cancer Society; Ildiko Medve and Adria Sai-Halasz EGFR Lung Cancer Research Fund; Balassiano Family Fund for Lung Cancer Research
OSTI ID:
1569902
Journal Information:
Cancer Discovery, Journal Name: Cancer Discovery Journal Issue: 7 Vol. 9; ISSN 2159-8274
Publisher:
American Association for Cancer ResearchCopyright Statement
Country of Publication:
United States
Language:
ENGLISH

References (33)

Assessment of Resistance Mechanisms and Clinical Implications in Patients With EGFR T790M–Positive Lung Cancer and Acquired Resistance to Osimertinib journal November 2018
Erlotinib versus chemotherapy as first-line treatment for patients with advanced EGFR mutation-positive non-small-cell lung cancer (OPTIMAL, CTONG-0802): a multicentre, open-label, randomised, phase 3 study journal August 2011
Osimertinib for pretreated EGFR Thr790Met-positive advanced non-small-cell lung cancer (AURA2): a multicentre, open-label, single-arm, phase 2 study journal December 2016
Evaluating the utility of the HTRF® Transcreener™ ADP assay technology: A comparison with the standard HTRF assay technology journal August 2009
Structures of Lung Cancer-Derived EGFR Mutants and Inhibitor Complexes: Mechanism of Activation and Insights into Differential Inhibitor Sensitivity journal March 2007
An Allosteric Mechanism for Activation of the Kinase Domain of Epidermal Growth Factor Receptor journal June 2006
Lung Adenocarcinoma Harboring EGFR T790M and In Trans C797S Responds to Combination Therapy of First- and Third-Generation EGFR TKIs and Shifts Allelic Configuration at Resistance journal November 2017
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M journal December 2009
Targeting Bcr–Abl by combining allosteric with ATP-binding-site inhibitors journal January 2010
Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors journal May 2016
The allosteric inhibitor ABL001 enables dual targeting of BCR–ABL1 journal March 2017
A small molecule–kinase interaction map for clinical kinase inhibitors journal February 2005
Acquired EGFR C797S mutation mediates resistance to AZD9291 in non–small cell lung cancer harboring EGFR T790M journal May 2015
Amplification of EGFR T790M causes resistance to an irreversible EGFR inhibitor journal February 2010
Activating Mutations in the Epidermal Growth Factor Receptor Underlying Responsiveness of Non–Small-Cell Lung Cancer to Gefitinib journal May 2004
Gefitinib or Carboplatin–Paclitaxel in Pulmonary Adenocarcinoma journal September 2009
Improved Overall Survival in Melanoma with Combined Dabrafenib and Trametinib journal January 2015
Pertuzumab, Trastuzumab, and Docetaxel in HER2-Positive Metastatic Breast Cancer journal February 2015
Osimertinib or Platinum–Pemetrexed in EGFR T790M–Positive Lung Cancer journal February 2017
Osimertinib in Untreated EGFR -Mutated Advanced Non–Small-Cell Lung Cancer journal January 2018
The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP journal January 2008
Clinical and Biological Features Associated With Epidermal Growth Factor Receptor Gene Mutations in Lung Cancers journal March 2005
EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy journal June 2004
Cetuximab Response of Lung Cancer–Derived EGF Receptor Mutants Is Associated with Asymmetric Dimerization journal September 2013
Analysis of Tumor Specimens at the Time of Acquired Resistance to EGFR-TKI Therapy in 155 Patients with EGFR -Mutant Lung Cancers journal March 2013
EGFR Mutations and Resistance to Irreversible Pyrimidine-Based EGFR Inhibitors journal May 2015
Intratumoral Epiregulin Is a Marker of Advanced Disease in Non–Small Cell Lung Cancer Patients and Confers Invasive Properties onEGFR-Mutant Cells journal July 2008
AZD9291, an Irreversible EGFR TKI, Overcomes T790M-Mediated Resistance to EGFR Inhibitors in Lung Cancer journal June 2014
Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer journal October 2006
Phase III Study of Afatinib or Cisplatin Plus Pemetrexed in Patients With Metastatic Lung Adenocarcinoma With EGFR Mutations journal September 2013
Osimertinib in Pretreated T790M-Positive Advanced Non–Small-Cell Lung Cancer: AURA Study Phase II Extension Component journal April 2017
Osimertinib As First-Line Treatment of EGFR Mutation–Positive Advanced Non–Small-Cell Lung Cancer journal March 2018
Oncogene Mutations, Copy Number Gains and Mutant Allele Specific Imbalance (MASI) Frequently Occur Together in Tumor Cells journal October 2009

Cited By (2)

Current Approaches in NSCLC Targeting K-RAS and EGFR journal November 2019
Resistance mechanisms to osimertinib in EGFR-mutated non-small cell lung cancer journal September 2019

Similar Records

The T790M mutation in EGFR kinase causes drug resistance by increasing the affinity for ATP
Journal Article · Tue Jul 15 00:00:00 EDT 2008 · Proc. Natl. Acad. Sci. USA · OSTI ID:1006519
Crystal structure of EGFR T790M/C797S/V948R in complex with EAI045
Journal Article · Sun Jul 15 00:00:00 EDT 2018 · Biochemical and Biophysical Research Communications · OSTI ID:23105732
Novel mutant-selective EGFR kinase inhibitors against EGFR T790M
Journal Article · Mon Jan 11 23:00:00 EST 2010 · Nature · OSTI ID:1006040

Related Subjects

60 APPLIED LIFE SCIENCES