T790m MutationEdit
The T790M mutation is a specific genetic change in the epidermal growth factor receptor (EGFR) gene that plays a central role in a subset of non-small cell lung cancer (NSCLC). This mutation substitutes methionine for threonine at position 790 in the receptor and is best understood as a classic mechanism of acquired resistance. In patients whose tumors carry activating EGFR mutations and who initially respond to first- or second-generation EGFR tyrosine kinase inhibitors (TKIs) such as gefitinib or erlotinib, the appearance of T790M often signals that the cancer is finding a new way to drive growth despite therapy.
In scientific and clinical discourse, T790M is widely recognized as a major clinical turning point. It helped catalyze a shift from first-line strategies that briefly suppressed disease to the development of next-generation inhibitors designed to work even after resistance has emerged. This transition is exemplified by the introduction of third-generation EGFR TKIs, which include drugs engineered to target both activating EGFR mutations and the T790M resistance alteration while sparing normal cells. The practical impact is that patients who progress on earlier TKIs can often experience renewed disease control when treated with these newer agents. For discussion of the broader context, see EGFR and non-small cell lung cancer.
Biological basis
Genetic and molecular features - The T790M mutation occurs in the EGFR gene, a receptor that, when activated, stimulates signaling pathways promoting tumor cell survival and proliferation. The mutation is most commonly studied in the context of NSCLC that initially harbors activating mutations in EGFR, such as L858R or exon 19 deletions. In many cases, T790M arises after exposure to EGFR TKIs, representing an adaptive change by tumor cells to overcome therapeutic pressure. See EGFR and non-small cell lung cancer for background.
Mechanism of resistance - T790M alters the ATP-binding pocket of the EGFR kinase domain. This change increases the receptor’s affinity for ATP, which reduces the ability of first- and second-generation TKIs to competitively inhibit signaling. The result is continued downstream signaling and tumor growth despite therapy. For a broader discussion of resistance mechanisms, refer to drug resistance and tyrosine kinase inhibitors.
Clinical implications - Detection of T790M after progression on a first- or second-generation EGFR TKI guides subsequent treatment. If the mutation is present, a third-generation EGFR TKI is typically recommended, since these agents are designed to inhibit mutant EGFR carrying T790M while minimizing activity against wild-type EGFR. This approach has altered the standard of care in many health systems and has influenced guidelines and diagnostic pathways. See re-biopsy and circulating tumor DNA for related diagnostic methods.
Detection and diagnosis
Tissue and liquid biopsy - Confirmation of T790M can be achieved through tumor tissue re-biopsy or through noninvasive liquid biopsy that detects circulating tumor DNA (ctDNA). Liquid biopsy has become increasingly common because it reduces procedural risk and can capture the heterogeneity of resistance mutations across a patient’s cancer. Diagnostic platforms include polymerase chain reaction (PCR)-based assays and next-generation sequencing (NGS), each with its own sensitivity profile. See circulating tumor DNA and liquid biopsy for detailed discussions.
Clinical decision-making - Once T790M is detected, physicians typically transition to a third-generation EGFR TKI, such as osimertinib, which has demonstrated superior progression-free survival compared with chemotherapy in this setting. Ongoing monitoring is essential to detect further resistance and to manage treatment-related adverse effects. See osimertinib for the therapy most closely associated with targeting T790M.
Treatment and resistance management
Third-generation EGFR TKIs - Osimertinib is the best-known example of a therapy designed to overcome T790M-mediated resistance while offering activity against common activating EGFR mutations. It has become a standard option for patients who progress on first- or second-generation TKIs and are found to carry T790M. See osimertinib.
Emergence of additional resistance - Even with third-generation inhibitors, tumors can develop new resistance mechanisms, including mutations such as C797S that hinder drug binding, or alternative pathway alterations that bypass EGFR signaling. When resistance to osimertinib occurs, subsequent treatment decisions may involve chemotherapy regimens or participation in clinical trials exploring novel agents and combinations. See C797S mutation and drug resistance for broader context.
Epidemiology and impact
Prevalence and patient populations - Among patients with activating EGFR mutations who experience progression on first-generation TKIs, roughly half to two-thirds harbor T790M as a resistance mechanism, though exact figures vary by cohort and testing method. The prevalence of activating EGFR mutations in NSCLC is higher in certain populations, notably among never-smokers and in some ethnic groups, which shapes diagnostic and therapeutic strategies. See non-small cell lung cancer for epidemiology and risk considerations.
Clinical outcomes and policy implications - The identification of T790M and the availability of targeted therapies have improved outcomes for a substantial subset of patients with NSCLC. At the same time, the high cost of third-generation inhibitors and the need for repeat testing raise questions about access, affordability, and the optimal allocation of healthcare resources. In debates about drug pricing and innovation, advocates argue that robust IP protections and market-driven competition spur breakthroughs, while critics contend that high prices limit patient access and may distort incentives. See pharmaceutical pricing and patents for related discussions.
Controversies and policy debates
Innovation versus access - A central policy debate centers on how best to balance rewarding pharmaceutical innovation with broad patient access. Proponents of market-based systems emphasize the role of patent protection and price signals in funding research, development, and clinical trials that yield discoveries like the T790M-targeting approach. Critics argue that exorbitant prices restrict use of life-saving therapies and advocate for negotiation, value-based pricing, or public options to improve affordability. See patents and pharmaceutical pricing.
Testing and diagnostic coverage - Requiring molecular testing for resistance mutations such as T790M raises questions about coverage, infrastructure, and turnaround times in health systems. Proponents note that precise, targeted therapy hinges on accurate detection, while skeptics warn that testing costs and access disparities can delay treatment. See precision medicine and circulating tumor DNA.
Regulatory pathways and competition - Accelerated approvals and post-market requirements aim to get effective therapies to patients sooner, but critics worry about overpayment for drugs with uncertain long-term benefit. The pursuit of competition through generics and biosimilars is often cited as a way to lower costs, though it is contingent on patent life cycles and market dynamics. See FDA and biosimilar.
See also