The Epidermal Growth Factor Receptor (EGFR) plays a fundamental role in regulating cell growth, division, and survival. Located on cell surfaces, this protein acts like an antenna, receiving signals for cell multiplication and development. In healthy tissues, this process is tightly controlled, ensuring proper development and repair. However, mutations in the EGFR gene can disrupt this balance.
When the EGFR gene is mutated, the receptor can become overactive, continuously sending “grow and divide” signals. This uncontrolled cell proliferation is a defining characteristic of cancer, particularly non-small cell lung cancer (NSCLC), the majority of lung cancer cases. The discovery of these specific mutations has led to the development of targeted therapies to block the mutated EGFR protein’s activity. While promising, cancer cells can adapt, leading to drug resistance.
The T790M Mutation Explained
The T790M mutation is a specific alteration in the EGFR gene that frequently emerges in NSCLC patients who have been treated with first- or second-generation EGFR inhibitor drugs. This mutation involves a single amino acid change at position 790 in the EGFR protein, where a Threonine (T) residue is replaced by a Methionine (M) residue. This change alters the drug’s binding site within the EGFR protein’s ATP-binding pocket.
The T790M mutation makes it harder for first-generation inhibitors like gefitinib (Iressa) and erlotinib (Tarceva), or second-generation inhibitors such as afatinib (Gilotrif) and dacomitinib, to bind effectively to the EGFR protein. This reduced binding affinity renders these therapies ineffective, allowing uncontrolled growth. The T790M mutation is rarely present when lung cancer is first diagnosed. Instead, it typically develops as an acquired resistance mechanism after a period of successful treatment, often leading to disease progression within 8 to 16 months of initial therapy.
Detecting the T790M Mutation
Identifying the T790M mutation is an important step when resistance to initial EGFR targeted therapies is suspected. Physicians commonly use two primary methods for detection. The first is a traditional tissue biopsy, which involves obtaining a tumor sample for genetic analysis. This method directly analyzes the tumor’s genetic makeup and is considered definitive.
An alternative is the less invasive liquid biopsy, which analyzes a blood sample for circulating tumor DNA (ctDNA). Cancer cells, including those with the T790M mutation, shed fragments of their DNA into the bloodstream, which can then be detected. Liquid biopsies offer advantages such as being easier to perform and less demanding for the patient compared to a tissue biopsy. While often faster and more convenient, liquid biopsies can sometimes be less sensitive than tissue biopsies, and may not detect the mutation if ctDNA levels are very low.
Targeted Therapy for T790M
The emergence of the T790M mutation as a common resistance mechanism led to newer treatments. Third-generation EGFR inhibitors were designed to overcome this challenge. Osimertinib (Tagrisso) is a prominent example of this class of drugs. This medication works by irreversibly binding to and inhibiting the EGFR protein, even when the T790M mutation is present.
Osimertinib demonstrates high selectivity for both the original activating EGFR mutations and the acquired T790M mutation, with less effect on healthy EGFR. This selectivity helps minimize side effects often associated with earlier generation inhibitors. Initially, osimertinib received approval for patients with T790M mutation after progression on first- or second-generation EGFR inhibitors. However, clinical trials, such as the FLAURA study, have since shown its superior efficacy as a first-line treatment for newly diagnosed EGFR-mutated NSCLC, leading to longer progression-free survival compared to older therapies. This shift in treatment strategy aims to preemptively delay the development of T790M resistance, improving initial outcomes for patients.
Prognosis and Future Directions
The introduction of third-generation EGFR inhibitors like osimertinib has improved the outlook for patients with NSCLC harboring the T790M mutation. These targeted therapies have extended progression-free survival and, in some cases, overall survival, offering a more effective option than traditional chemotherapy. Patients treated with osimertinib as a first-line therapy can experience a progression-free survival of approximately 19 to 22 months.
Despite these advancements, cancer cells can eventually develop further resistance mechanisms even to third-generation inhibitors. Researchers are investigating these new resistance pathways, including additional EGFR mutations like C797S or activation of alternative signaling pathways. Ongoing research focuses on developing next-generation treatments, such as fourth-generation EGFR inhibitors, and exploring combination therapies to address these evolving resistance patterns, to further extend the benefits of targeted treatment.