Understanding Resistance to EGFR Inhibitors—Impact on Future Treatment Strategies

Deric L. Wheeler; Emily F. Dunn; Paul M. Harari

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In This Article

Resistance to EGFR TKIs

Despite excellent clinical response to EGFR TKIs in NSCLC patients harboring mutations in the catalytic domain, acquired resistance following initial response often manifests within 6–12 months of therapy.[31] Pao et al.[77] reported that molecular analysis of EGFR in patients with acquired resistance to gefitinib or erlotinib contain a secondary mutation in exon 20, which leads to substitution of methionine for threonine at position 790 (T790M) in the kinase domain.[77,79] T790M of EGFR is considered to be the 'gatekeeper' residue, which is an important determinant of inhibitor specificity in the ATP-binding pocket of EGFR. Substitution of this residue in EGFR with a bulky methionine may cause resistance by steric interference with binding of TKIs, including gefitinib and erlotinib.[77–79] However, further research on this mutation has shown that it may cause resistance to these agents by increasing the affinity for ATP.[128] Since these reports were published, several studies have shown that the T790M mutation is actually present before the patient commences initial therapy.[129] This finding suggests that this mutation may confer a survival advantage to the tumor and is probably selected for while the patient is receiving anti-EGFR TKI treatment.[129–133] The identification of the EGFR T790M mutation has led to preclinical and clinical development of irreversible EGFR TKIs to effectively target this mechanism of resistance.[78]

An activating mutation of KRAS is present in 15–30% of NSCLC.[134,135] Unlike the somatic mutations that arise in EGFR in non-smokers, KRAS mutations are highly prevalent in smoking-associated tumors.[136,137] These mutations in KRAS may be a marker of primary resistance to both gefitinib and erlotinib.[138]

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