Resistance to EGFR tyrosine kinase inhibitors in lung adenocarcinoma is most commonly due to:

The T790M mutation in EGFR is the most common mechanism of acquired resistance to first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) in lung adenocarcinoma. This point mutation occurs in the EGFR kinase domain, leading to increased affinity for ATP and reduced binding of the TKIs, thereby diminishing their inhibitory effect. Identifying T790M mutation is crucial as it guides the use of third-generation TKIs like osimertinib, which specifically target this resistant mutation and improve patient outcomes. Understanding and detecting T790M helps tailor targeted therapy and manage resistance effectively.

Reference: Holland-Frei Cancer Medicine, DeVita, Hellman, Rosenberg, 9th Edition.