EGFR T790M (resistant mutant, selective over wild-type EGFR)

Class

Third-generation EGFR tyrosine kinase inhibitor

Pathway

Potently inhibits EGFR T790M-resistant and sensitizing mutants while sparing wild-type EGFR

EGFR (epidermal growth factor receptor) is a receptor tyrosine kinase that, when activated by growth-factor binding, switches on intracellular signaling cascades controlling cell division and survival. In certain non-small cell lung cancers, mutations within the EGFR kinase domain make tumor growth dependent on this signaling, and earlier-generation inhibitors that block the ATP-binding site can shrink such tumors substantially. Over time, many tumors acquire a secondary mutation, threonine-790-to-methionine (T790M), within the kinase domain. This 'gatekeeper' change increases the receptor's affinity for ATP and sterically blocks earlier inhibitors from binding, restoring signaling and producing acquired drug resistance. Third-generation EGFR inhibitors are designed to potently block both the original activating mutations and this resistant T790M variant, while largely sparing normal, unmutated EGFR found in tissues such as skin and gut. This selectivity aims to maintain antitumor activity once resistance emerges while limiting the toxicity that comes from broadly inhibiting EGFR throughout the body. The mechanism is broadly relevant wherever oncogene-driven EGFR signaling sustains tumor growth and where secondary kinase-domain mutations erode the effectiveness of earlier therapies.