A genetic mutation is a permanent alteration in the DNA sequence of a gene, impacting how it functions and potentially leading to altered protein production or activity. The T790M mutation is a specific DNA change that has garnered significant attention in medical research due to its implications in certain diseases.
Understanding the T790M Mutation
The Epidermal Growth Factor Receptor (EGFR) is a protein on the surface of cells, playing a role in cell signaling pathways that regulate cell division and survival. Normally, EGFR binds to growth factors, instructing cells to grow and divide in a controlled manner. However, mutations in the EGFR gene can disrupt this balance, leading to uncontrolled cell growth.
These mutations are particularly relevant in non-small cell lung cancer (NSCLC), where they act as “driver mutations” that promote tumor growth. The T790M mutation is a specific point mutation within the EGFR gene, located at codon 790 of exon 20. This mutation involves the substitution of a threonine amino acid with a methionine.
Impact on Targeted Cancer Treatment
Initial EGFR-targeted therapies, known as tyrosine kinase inhibitors (TKIs), block signaling pathways driven by mutated EGFR. First-generation TKIs like gefitinib and erlotinib reversibly bind to the EGFR kinase domain, inhibiting ATP binding and hindering cell proliferation. Second-generation TKIs, such as afatinib and dacomitinib, bind irreversibly to the EGFR kinase domain, offering a broader inhibition of kinases. These therapies have improved progression-free survival in patients with EGFR-mutant NSCLC compared to chemotherapy.
Despite initial positive responses, patients often develop acquired resistance to these TKIs. The T790M mutation is the most common mechanism of this acquired resistance, occurring in 50% to 60% of patients after initial TKI therapy. This mutation increases the EGFR receptor’s affinity for ATP, making it more difficult for TKIs to bind and inhibit the receptor, allowing cancer cells to resume growth. The emergence of T790M limits the long-term efficacy of these targeted treatments.
Identifying the T790M Mutation
Detecting the T790M mutation guides treatment decisions. Two primary methods are used: tissue biopsies and liquid biopsies. Tissue biopsies involve obtaining a sample directly from the tumor, often from the lung, and are accurate for detecting the T790M mutation. However, they are invasive procedures, carrying risks of complications and limitations in obtaining samples.
Liquid biopsies are less invasive, involving a blood test to detect circulating tumor DNA (ctDNA) released by cancer cells. This method offers convenience and allows for repeat testing to monitor disease progression and resistance. While convenient, their sensitivity for detecting T790M can be lower than tissue biopsies, potentially leading to false negative results. A positive liquid biopsy result is generally sufficient to guide treatment, but a negative result may still warrant a confirmatory tissue biopsy.
Treatment Approaches for T790M
The emergence of the T790M mutation necessitated new therapeutic strategies to overcome acquired resistance. This led to the development of third-generation EGFR TKIs, such as osimertinib. These agents are specifically designed to target both the original activating EGFR mutations and the T790M resistance mutation.
Osimertinib works by irreversibly binding to the ATP-binding pocket of the EGFR kinase domain, effectively inhibiting the mutated receptor, including the T790M variant. It also demonstrates high selectivity for mutant EGFR over wild-type (healthy) EGFR, which helps to minimize side effects seen with earlier TKIs. Clinical trials have shown that osimertinib improves progression-free survival in patients with T790M-positive NSCLC who have progressed on first- or second-generation TKIs, extending to approximately 10.1 months compared to 4.4 months with chemotherapy. Osimertinib is now a standard treatment option for patients with T790M-positive advanced NSCLC.