T790M Mutation

Definition

T790M is a specific resistance mutation in the EGFR gene (epidermal growth factor receptor), most commonly found in non-small cell lung cancer (NSCLC), particularly adenocarcinoma.

Clinical Context

• Seen in patients with EGFR-mutant NSCLC who initially respond to first- or second-generation EGFR TKIs (like erlotinib, gefitinib, or afatinib).
• About 50–60% of patients who develop resistance to these drugs acquire the T790M mutation.

Mechanism:

• T790M is a point mutation at exon 20 of the EGFR gene.
• It changes threonine (T) to methionine (M) at position 790.
• This mutation increases ATP affinity in the EGFR binding site, reducing TKI effectiveness.

Pharmacologic Implications:

• Osimertinib (Tagrisso) is a third-generation EGFR TKI designed to overcome T790M-mediated resistance.
  • Irreversibly binds mutant EGFR including T790M.
  • Crosses the blood-brain barrier – beneficial in CNS metastases.
• Pharmacists must monitor: QTc prolongation, Interstitial lung disease (ILD), Cardiomyopathy, Drug-drug interactions (CYP3A4 metabolism)

Testing: Liquid biopsy (ctDNA) or tumor biopsy is used to detect the T790M mutation after progression on earlier EGFR TKIs.