Previously Funded Research

Matthew Meyerson, MD, PhD

Dana-Farber Cancer Institute & Harvard Medical School

Research Project:

A novel therapeutic combination strategy to eradicate EGFR-mutant cancer persisters

Summary:

Team Science Co-Awardees
Principal Investigator: Kwok-Kin Wong, MD, PhD, Perlmutter Cancer Center / New York University

Project 1:
Lead: Kwok-Kin Wong, MD, PhD, Perlmutter Cancer Center / New York University
Co-investigator: Lior Golomb, PhD, Dana-Farber Cancer Institute

Project 2:
Lead: Matthew Meyerson, MD, PhD, Dana-Farber Cancer Institute & Harvard Medical School
Co-investigator: Elaine Shum, MD, New York University
Co-investigator: Jiehui Deng, PhD, New York University
Project coordinator: Kristen Labbe, MPH, Perlmutter Cancer Center, New York University
Patient advocate: Deborah Markow

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Lung cancer is the leading contributor to cancer death worldwide. A major type of lung cancer called lung adenocarcinoma (LUAD) often carries mutations in a gene called epidermal growth factor receptor (EGFR). These mutations are found in about 10% of lung cancers among people of European or African ancestry, and up to 45% among those of East Asian ancestry. A particular class of oral drugs known as tyrosine kinase inhibitors (TKIs), such as osimertinib, can target the EGFR mutation in lung cancer cells and have dramatically improved outcomes for patients. Despite this advancement, almost all patients with advanced disease eventually see their cancer return due to drug resistance. Although osimertinib taken on its own is currently one of the most effective EGFR-targeting drugs available, the average survival is still only about 39 months.

The development of drug resistance and cancer recurrence can happen in several ways. In some cases, the EGFR gene itself acquires an additional mutation that prevents the drug from working. Other times, the cancer activates alternate pathways that allow the cancer to grow or even change its identity, transforming the cancer cell from an adenocarcinoma into small-cell or squamous-cell lung cancer. However, in nearly half of all patients who relapse, doctors cannot pinpoint the exact cause. These “hidden” resistance mechanisms remain one of the biggest challenges in treating EGFR-mutant lung cancer.

Our research team aims to prevent this resistance before it starts. Rather than allowing the cancer to form new escape routes and then trying to block them one by one, our strategy is to begin treatment with a combination therapy that can kill more cancer cells from the start, reducing the chance that any resistant cells can develop. We believe this approach can lead to deeper, more durable responses and ultimately help patients live longer.

In a screen to determine other genes we could target to improve therapeutic outcomes, we identified a gene called SLC33A1, which, when turned off or inactivated, made cancer cells more sensitive to osimertinib and prevented them from entering a drug-resistant state. Our data suggests that SLC33A1 inactivation impacted two major cancer survival pathways, the EGFR/Ras/MAPK pathway, which drives tumor growth, and the NRF2 oxidative stress response, which helps cells resist damage from therapy. However, because there are no drugs that directly inhibit SLC33A1, we searched for medicines that could mimic the same cellular effect. We found that several macrocyclic compounds, in particular, cyclosporine A and others, NIM811, alisporivir, and voclosporin, can produce the same effect as seen with SLC33A1 inactivation. These findings suggest that combining osimertinib with certain macrocycles could overcome drug tolerance in EGFR-mutant lung cancer.

This research program is divided into two projects. The first project (Project 1/Aim 1) tests the combination of osimertinib and macrocyclic drugs in pre-clinical models, with a particular focus on administering CsA (with osimertinib) in mouse models that closely replicate human lung cancer. In doing so, from Project 1, we will not only learn about the biological and disease impacts of CsA (with osimertinib) but also begin to learn how CsA functions in the cell and what it targets. The second part of the research program (Project 2/Aim 2) aims to assess the combination of osimertinib and CsA in the clinic and its impact on human lung cancer. We plan to launch a phase II clinical trial testing the combination of these drugs in patients with high-risk EGFR-mutant non-small cell lung cancer (NSCLC).

The osimertinib and CsA combination is unique in that it is an all-oral regimen that has fewer potential side effects and is easier to administer than what is currently available. Presently, there are two FDA-approved combination therapies for EGFR-mutant lung cancer: 1) osimertinib plus chemotherapy, and 2) a dual-antibody and TKI combination (amivantamab with lazertinib). Both have improved patient outcomes, with average progression-free survival ranging from 23 to 26 months and overall survival exceeding 47 months. However, these regimens often cause severe side effects such as nausea, fatigue, rashes, low blood counts, and infusion reactions, which can significantly affect quality of life. Chemotherapy and amivantamab also are given intravenously. CsA is already an FDA-approved drug used safely for decades to prevent rejection in patients who have received organ transplants and to treat autoimmune disorders. It has a well-understood pharmacology and a manageable safety profile, with the most common side effects being elevated blood pressure and kidney strain. We believe that repurposing this familiar drug for lung cancer could offer a practical and more tolerable way to enhance osimertinib’s effectiveness.

In summary, this research seeks to (i) determine the target(s) of CsA and understand how it and related macrocycles enhance EGFR TKI therapy (osimertinib), (ii) characterize the efficacy of the osimertinib and CsA drug combination in lung cancer animal models, and (iii) conduct a phase II clinical trial assessing the efficacy of this new combination therapy in patients with lung cancer with the EGFR mutation to eliminate cancer and prevent cancer recurrence.