Epidermal growth factor receptor (EGFR) mutant forms (EGFR)

The Epidermal Growth Factor Receptor (EGFR) is a transmembrane protein and a member of the ErbB family of receptor tyrosine kinases [UniProt]. It plays a vital role in regulating cell proliferation, survival, and differentiation through the activation of downstream signaling pathways like PI3K/Akt and MAPK [NIH]. In many cancers, particularly non-small cell lung cancer (NSCLC), somatic mutations in the EGFR kinase domain lead to constitutive activation and oncogenic transformation [PubMed]. While first-generation tyrosine kinase inhibitors (TKIs) initially show efficacy, most patients eventually develop resistance, most commonly through the T790M gatekeeper mutation [NIH].\n\nThe T790M mutation increases the receptor's affinity for ATP, thereby reducing the effectiveness of reversible inhibitors [PubMed]. Third-generation TKIs, such as osimertinib, were developed to specifically target these mutant forms, including T790M, by forming an irreversible covalent bond with the Cys797 residue in the ATP-binding pocket [NIH]. These agents are designed to spare wild-type EGFR, which helps minimize off-target toxicities like severe skin rash and diarrhea [FDA]. However, clinical challenges remain, including the emergence of further resistance mutations like C797S and the risk of interstitial lung disease [PubMed].

Other names

HER1ERBBERBB1PIG61mEGFREpidermal growth factor receptor T790M

Irreversible inhibition of the tyrosine kinase domain of mutant EGFR by covalent binding to Cys797, specifically targeting the T790M gatekeeper mutation while sparing wild-type EGFR.