Mechanism of delayed resistance (6–24 months)

Biopsy and mutational analysis of individual nodules show multiple clonal origins with distinct mutational changes.

Secondary mutations are found in 50–70% of patients who progress and only in patients with initial KIT/PDGFRA mutations especially KIT exon 11.

T670I “gatekeeper” is the most common secondary mutation. Other mutations are in exon 14, 17, and 18. No secondary mutations have been documented in wild-type tumors.

Major mechanisms of imatinib resistance are (1) secondary mutation in KIT or PDGFRA in addition to the initial mutation, (2) overexpression of KIT as evidenced by genomic amplification, (3) activation of alternate pathways and loss of KIT, and (4) functional resistance, defined as mutations in regions of KIT or PDGFR that are not bound by imatinib.

Patients who progress on 400 mg may benefit with 800 mg of imatinib.