The T790M mutation is a genetic alteration that can occur in cancer cells. This mutation is particularly relevant in the context of certain cancer treatments. It represents a change in the genetic code that can affect how cancer cells respond to therapies.
Understanding T790M
The T790M mutation is an acquired genetic change, developing over time rather than being inherited. It occurs as a point mutation within the epidermal growth factor receptor (EGFR) gene, located on exon 20. This mutation is a common mechanism of acquired resistance to first and second-generation EGFR tyrosine kinase inhibitors (TKIs) in non-small cell lung cancer (NSCLC).
The presence of T790M alters the EGFR protein’s structure, affecting how it interacts with TKI drugs. This alteration can increase the EGFR’s affinity for ATP, a molecule that fuels cell growth, thereby reducing the effectiveness of TKIs which compete with ATP for binding to the receptor. This makes the cancer cells less responsive to the initial targeted therapy, leading to disease progression in patients who were previously responding to treatment.
How T790M Develops
The T790M mutation arises in cancer cells as a response to the selective pressure exerted by initial EGFR TKI treatments. When cancer patients receive first or second-generation EGFR TKIs, these drugs inhibit the growth of cancer cells that lack the T790M mutation. However, some cancer cells may spontaneously develop this mutation during treatment.
These mutated cells gain a survival advantage, evading the drug’s effects. As the drug continues to suppress the growth of non-mutated cells, the T790M-positive cells proliferate, becoming the dominant population within the tumor. This explains why T790M is an acquired resistance mechanism, emerging after 10 to 16 months of initial TKI therapy.
Identifying T790M
Accurate identification of the T790M mutation is important for guiding subsequent treatment decisions. Two primary methods are used for detection: tissue biopsy and liquid biopsy. Tissue biopsy involves obtaining a sample of the tumor directly, often through a re-biopsy after initial treatment failure. It is considered the gold standard, providing histological information and a direct assessment of the tumor’s genetic makeup.
Despite its accuracy, tissue biopsy is an invasive procedure that can be challenging or risky depending on the tumor’s location or size. Liquid biopsy, analyzing circulating tumor DNA (ctDNA) from a blood sample, offers a less invasive alternative. While less sensitive than tissue biopsy, it is easier to perform and can provide insights into tumor heterogeneity. A negative liquid biopsy result does not definitively rule out the mutation, and a subsequent tissue biopsy may be recommended if clinical suspicion remains high.
Treatment Approaches for T790M
The development of the T790M mutation in non-small cell lung cancer patients treated with first or second-generation EGFR TKIs led to the need for new therapeutic strategies. This led to the development of third-generation EGFR TKIs, such as osimertinib. Osimertinib targets both the original activating EGFR mutations and the T790M resistance mutation.
This drug works by forming a covalent bond with a specific cysteine residue (Cys797) in the EGFR kinase domain, overcoming the resistance. Clinical trials show that osimertinib significantly extends progression-free survival in T790M-positive advanced NSCLC, with a median progression-free survival of approximately 10.1 months compared to 4.4 months with chemotherapy. Osimertinib is recommended as a second-line treatment for patients whose tumors develop the T790M mutation after initial EGFR TKI therapy. It has also shown effectiveness against brain metastases due to its ability to cross the blood-brain barrier.