Allosteric EGFR Inhibition May Improve Outcomes for Non-Small Cell Lung Cancer

Project Overview

• The Epidermal Growth Factor Receptor (EGFR) protein plays a crucial role in normal cell processes, including growth and survival. However, in the context of cancer, mutated EGFR contributes to tumor growth and progression, particularly in non-small cell lung cancer (NSCLC).
• Three generations of FDA-approved drugs target mutated EGFR but resistance has emerged to these therapies.
• Scientists at Dana-Farber have created a portfolio of mutant-selective fourth-generation EGFR inhibitors, including a development candidate, EAI-432.
• The EGFR inhibitor portfolio is available for licensing to expedite the development of therapeutic compounds against cancer.

Technology

About one-third of patients with non-small cell lung cancer (NSCLC) have a mutation in the EGFR gene. Mutated EGFR is also found in other cancers, including lung adenocarcinoma, conventional glioblastoma multiforme, glioblastoma, and colon adenocarcinoma, and has been the target of three generations of FDA-approved drugs. However, even with third-generation EGFR inhibitors, such as osimertinib, which have changed the standard of care for NSCLC patients, new resistance mutations have emerged, forcing patients to resort to chemotherapy or ablation methods for destroying cancerous tissue.

For the past 15 years, Michael Eck, MD, PhD, at Dana-Farber has pioneered the development of a new approach to targeting the latest EGFR mutations and overcoming resistance by developing an allosteric EGFR inhibitor. Unlike all of the approved EGFR inhibitors that bind to the ATP binding pocket in the enzyme’s active site, an allosteric inhibitor binds to a site distinct from the active site and induces structural or other dynamic changes in the protein thereby affecting its function. Today, in partnership with Pasi Jänne and David Scott, the team has developed exquisitely potent and selective allosteric EGFR inhibitors, including development candidate EAI-432. EAI-432 may prove effective as a single agent for some indications but also has the potential to be used in combination with existing drugs.  

Allosteric EGFR inhibition represents a unique “double-drugging” strategy by binding outside the ATP pocket. The combination of EAI-432 and third-generation EGFR inhibitors like osimertinib may deliver enhanced anti-tumor effects and delay the emergence of resistance. With the allosteric approach combined with the traditional ATP-site approach, both inhibitors can bind simultaneously, and if one dissociates, the receptor remains inhibited. Only the allosteric approach allows for double-drugging of the mutant receptor.

In 2023, the team published preclinical data on EAI-432, showing that it is effective in mice against tumors harboring the common L858R EGFR mutation in NSCLC, as well as the subsequent resistance mutations that emerge after treatment with current therapies. EAI-432 is also effective in a mouse tumor model that represents brain metastases. 

The path to developing EAI-432 at Dana-Farber has involved academic and industry collaborations (Takeda), now centered in the Dana-Farber laboratories of Michael Eck, David Scott, and Pasi Jänne. The Mark Foundation for Cancer Research (MFCR) has provided major funding and scientific input to support the IND-enabling studies, with additional funding from the Blavatnik Family Foundation.

Team Members: Michael Eck, MD, PhD, David Scott, PhD, Pasi Jänne, MD, PhD

Applications

Allosteric inhibition with EAI-432 offers a potential new treatment path for EGFR-mutated NSCLC. This fourth-generation EGFR inhibitor has a good oral pharmacokinetic profile, is brain-penetrant, and was designed to target L858R EGFR-mutated cancers as a monotherapy and in combination with third-generation EGFR inhibitors, like osimertinib. Preclinical data also shows that EAI-432 is potent against mutants resistant to first-generation (gefitinib) and third-generation agents. 

Opportunities

Dana-Farber’s allosteric EGFR inhibitor portfolio, including EAI-432, is available for licensing.

Team Members

Michael Eck, MD, PhD

Professor, Cancer Biology, Dana-Farber

Professor of Biological Chemistry and Molecular Pharmacology, Harvard Medical School

Michael's Bio

David Scott, PhD

Director, Medicinal Chemistry Core, Dana-Farber

David's Bio

Pasi Jänne, MD, PhD

Senior Vice President for Translational Medicine, and David Livingston, MD Chair, Dana-Farber

Professor of Medicine, Harvard Medical School

Pasi's Bio