Molecularly guided therapy in gastrointestinal malignancies: From established targets to resistance and emerging precision strategies

Table 5 KIT proto-oncogene receptor tyrosine kinase- and platelet-derived growth factor receptor alpha-targeted therapies in gastrointestinal stromal tumors

Molecular alteration	Approximate frequency	Preferred targeted therapy	Clinical role	Evidence grade	Resistance/emerging strategy	Representative sources
KIT exon 11 mutation	60%–70%	Imatinib 400 mg/day	Established first-line therapy; generally associated with the greatest sensitivity to imatinib	A	Secondary KIT mutations, clonal evolution, and acquired resistance; molecular reassessment may guide subsequent therapy	Li and Raut[104]; Wang et al[105]
KIT exon 9 mutation	10%–15%	High-dose imatinib 800 mg/day	Dose escalation may improve disease control, particularly in advanced disease	A	Secondary KIT mutations and clonal evolution; NGS-guided treatment selection and sequencing	Li and Raut[104]; Jakhetiya et al[103]
PDGFRA D842V mutation	5%–6%	Avapritinib	Preferred targeted therapy; this genotype is characteristically resistant to imatinib	A	Secondary resistance and clonal evolution; molecular monitoring and resistance-directed strategies remain under investigation	Mazzocca et al[106]; Wang et al[105]
Other PDGFRA mutations	Rare	Imatinib or alternative therapy according to mutation subtype	Variable sensitivity based on the specific PDGFRA alteration	B	Mutation-specific sensitivity and resistance require detailed molecular characterization	Li and Raut[104]
Wild-type GIST, including SDH-deficient, NF1-associated, and BRAF-associated tumors	10%–15%	Individualized treatment and clinical-trial enrollment	Limited response to conventional KIT-directed TKIs; management depends on the underlying molecular subtype	C	Alternative molecular drivers and genotype-specific treatment strategies are under investigation	Schaefer et al[107]; Wang et al[105]
Secondary KIT/PDGFRA resistance mutations	Variable	Sequential TKI therapy guided by molecular profiling	Molecular characterization can support selection and sequencing of subsequent therapies	B	Intratumoral heterogeneity, polyclonal resistance, and clonal evolution	Li and Raut[104]; Wang et al[105]

Evidence classification: Grade A, established therapy supported by prospective randomized evidence and/or incorporated into clinical guidelines or routine standard-of-care practice; Grade B, clinically supported therapy based on prospective clinical studies: Non-randomized comparative studies: Or consistent clinical evidence with more limited validation; Grade C, emerging or investigational strategy supported by early-phase trials: Small prospective or retrospective studies: Or preliminary clinical data; Grade D, preclinical or experimental strategy supported primarily by laboratory or animal studies without sufficient clinical validation. Evidence grades describe the maturity and clinical validation of the evidence and do not necessarily indicate the magnitude of treatment benefit. BRAF: B-Raf proto-oncogene; GIST: Gastrointestinal stromal tumor; KIT: KIT proto-oncogene receptor tyrosine kinase; NF1: Neurofibromatosis type 1; NGS: Next-generation sequencing; PDGFRA: Platelet-derived growth factor receptor alpha; SDH: Succinate dehydrogenase; TKI: Tyrosine kinase inhibitor.