Previously Funded Research

Ximeng Liu, PhD

University of Texas MD Anderson Cancer Center

Research Project:

Deciphering response and resistance mechanisms to firmonertinib in NSCLC patients with EGFR PACC mutations

Summary:

Lung cancer is one of the most common types of cancer and remains the leading cause of cancer-related death worldwide. Non-small cell lung cancer (NSCLC) is the most common subtypes, accounting for about 85% of all lung cancer cases.

In about 30% of patients with late-stage NSCLC, the cancer is driven by mutations in a gene called epidermal growth factor receptor (EGFR). Drugs known as tyrosine kinase inhibitors (TKIs) are designed to bind and inhibit EGFR and stop cancer cells from growing. While these drugs can be effective, some patients do not respond to them from the start (a problem known as primary resistance), and others initially respond well but eventually stop benefiting from the treatment (acquired resistance). The drug resistance is a major reason why many patients with NSCLC have poor survival outcomes.

EGFR mutations can be divided into four groups. One of these groups named PACC mutations often have variable or poor response to current EGFR TKIs. A newer drug, firmonertinib, has shown encouraging results in clinical trials and may offer an effective treatment option for patients with EGFR PACC mutations.

This project aims to better understand why some patients with EGFR PACC mutations do not initially response to firmonertinib well (primary resistance) and to uncover why acquired resistance develops. These findings will lead to development of more effective treatment strategies and ultimately improve outcomes for patients with uncommon mutant NSCLC. Our preliminary data suggest that patients with EGFR PACC mutations respond differently to current clinically available EGFR TKIs and to the new drug firmonertinib. Building on these data, we will focus on investigate the primary resistance mechanism in Aim 1. We will analyze clinical data to determine whether patients with different types of PACC mutations, either single or multiple in the same tumor, have varied responses to firmonertinib. We will also examine patients’ genomic profiles to identify whether other genetic changes, such as mutations in additional genes, influence the firmonertinib response.

In Aim 2, we will explore the acquired resistance mechanism. Specifically, in Aim 2A, we will use an advanced approach called LentiMutate, which can quickly screen out the specific resistant mutations to a drug. We have already used this method successfully to discover mutations that cause resistance to osimertinib, one of the most commonly used EGFR TKIs and a standard treatment for NSCLC. We will apply this method to find resistant mutations to firmonertinib. In Aim 2B, we will use high-throughput sequencing techniques to discover potential genes that may drive resistance in our firmonertinib resistance cell models. Based on those findings, we will test whether combining firmonertinib with drugs that target these resistance-related genes can improve the ability to kill cancer cells in cellular experiments.

In Aim 2C, we will test the effect of these combination therapies in animal experiments. We will also pay attention to targets for which novel drugs are being tested in clinical settings, such as antibody-drug conjugates (ADCs), an innovative type of cancer therapy that links a monoclonal antibody to a chemotherapy drug to deliver drug directly to cancer cells. Additionally, we will explore the potential of combining firmonertinib with these ADCs in cellular and animal experiments.

If this project completes successfully, we will better understand why NSCLC patients with EGFR PACC mutations become resistant to firmonertinib. We will identify potential therapeutic targets in resistant tumors that could be treated with additional drugs. The combination of firmonertinib and these potential drugs will help patients overcome resistance and improve their survival time.